View source for LSm

{{Short description|Family of RNA-binding proteins}}
{{Technical|date=August 2013}}
[[File:LSm 1I5L 1.JPG|thumb|350px|The LSm protein Hfq hexamer torus showing the peptide backbone, with each protein in a different color, representing each beta strand as a ribbon, each alpha helix as a cylinder and the RNA oligonucleotide as a 300° arc]]
{{Infobox protein family
| Symbol = LSM
| Name = LSM domain
| image = PDB 1h64 EBI.jpg
| width =
| caption = crystal structure of the sm-related protein of p. abyssi the biological unit is a heptamer
| Pfam = PF01423
| Pfam_clan =
| InterPro = IPR001163
| SMART =
| PROSITE =
| MEROPS =
| SCOP = 1d3b
| TCDB =
| OPM family =
| OPM protein =
| CAZy =
| CDD = cd00600
}}
In [[molecular biology]], '''LSm proteins''' are a family of [[RNA]]-binding [[protein]]s found in virtually every cellular [[organism]].  LSm is a contraction of 'like Sm', because the first identified members of the LSm [[protein family]] were the '''Sm proteins'''.  LSm proteins are defined by a characteristic [[Protein tertiary structure|three-dimensional structure]] and their assembly into rings of six or seven individual LSm protein [[molecule]]s, and play a large number of various roles in [[mRNA]] processing and regulation.
The Sm proteins were first discovered as [[antigens]] targeted by so-called '''anti-Sm antibodies''' in a patient with a form of  [[systemic lupus erythematosus]] (SLE), a debilitating [[autoimmune disease]].  They were named Sm proteins in honor of Stephanie Smith, a patient who suffered from SLE.<ref name="Reeves_2003">{{cite journal | vauthors = Reeves WH, Narain S, Satoh M | title = Henry Kunkel, Stephanie Smith, clinical immunology, and split genes | journal = Lupus | volume = 12 | issue = 3 | pages = 213–7 | year = 2003 | pmid = 12708785 | doi = 10.1191/0961203303lu360xx | s2cid = 33112464 }}</ref>  Other proteins with very similar structures were subsequently discovered and named LSm proteins.  New members of the LSm protein family continue to be identified and reported.
Proteins with similar structures are grouped into a hierarchy of protein families, superfamilies, and folds.  The LSm protein structure is an example of a small [[beta sheet]] folded into a short barrel.  Individual LSm proteins assemble into a six or seven member doughnut ring (more properly termed a [[torus]]), which usually binds to a [[small RNA]] molecule to form a [[ribonucleoprotein]] complex.  The LSm torus assists the RNA molecule to assume and maintain its proper three-dimensional structure.  Depending on which LSm proteins and RNA molecule are involved, this ribonucleoprotein complex facilitates a wide variety of RNA processing including degradation, editing, splicing, and regulation.
Alternate terms for '''LSm family''' are '''LSm fold''' and '''Sm-like fold''', and alternate capitalization styles such as '''lsm''', '''LSM''', and '''Lsm''' are common and equally acceptable.
== History ==
=== Discovery of the Smith antigen ===
The story of the discovery of the first LSm [[protein]]s begins with a young woman, Stephanie Smith, who was diagnosed in 1959 with [[Lupus erythematosus|systemic lupus erythematosus (SLE)]], eventually succumbing to complications of the disease in 1969 at the age of 22.<ref name=Reeves_2003 /> During this period, she was treated at New York's [[Rockefeller University]] Hospital, under the care of Dr. Henry Kunkel and Dr. Eng Tan. As those with an [[Autoimmunity|autoimmune disease]], SLE patients produce [[Antibody|antibodies]] to [[antigen]]s in their [[Cell nucleus|cells' nuclei]], most frequently to their own [[DNA]]. However, Kunkel and Tan found in 1966 that Smith produced [[Antibody|antibodies]] to a set of nuclear proteins, which they named the 'smith [[antigen]]' ('''Sm Ag''').<ref name="pmid5932578">{{cite journal | vauthors = Tan EM, Kunkel HG | title = Characteristics of a soluble nuclear antigen precipitating with sera of patients with systemic lupus erythematosus | journal = J. Immunol. | volume = 96 | issue = 3 | pages = 464–71 | date = March 1966 | doi = 10.4049/jimmunol.96.3.464 | pmid = 5932578 | s2cid = 30325463 | doi-access = free }}</ref> About 30% of SLE patients produce antibodies to these proteins, as opposed to double stranded DNA. This discovery improved diagnostic testing for SLE, but the nature and function of this antigen was unknown.
=== Sm proteins, snRNPs, the spliceosome and messenger RNA splicing ===
Research continued during the 1970s and early 1980s.  The smith antigen was found to be a complex of ribonucleic acid ([[RNA]]) molecules and multiple proteins.  A set of [[uridine]]-rich [[Non-coding RNA|small nuclear RNA]] ('''snRNA''') molecules was part of this complex, and given the names '''[[U1 snRNA|U1]]''', '''[[U2 snRNA|U2]]''', '''[[U4 snRNA|U4]]''', '''[[U5 snRNA|U5]]''' and '''[[U6 snRNA|U6]]'''.  Four of these snRNAs (U1, U2, U4 and U5) were found to be tightly bound to several small proteins, which were named '''SmB''', SmD, '''SmE''', '''SmF''', and '''SmG''' in decreasing order of size.  SmB has an alternatively spliced variant, '''SmB'''', and a very similar protein, '''SmN''', replaces SmB'/B in certain (mostly neural) tissues.  SmD was later discovered to be a mixture of three proteins, which were named '''SmD1''', '''SmD2''' and '''SmD3'''.  These nine proteins (SmB, SmB', SmN, SmD1, SmD2, SmD3, SmE, SmF and SmG) became known as the '''Sm core proteins''', or simply '''Sm proteins'''.  The snRNAs are complexed with the Sm core proteins and with other proteins to form particles in the [[Cell nucleus|cell's nucleus]] called '''small nuclear ribonucleoproteins''', or [[snRNP]]s.  By the mid-1980s, it became clear that these '''snRNPs''' help form a large (4.8&nbsp;MD [[Molecular mass|molecular weight]]) complex, called the [[spliceosome]], around [[precursor mRNA|pre-mRNA]], excising portions of the pre-mRNA called [[intron]]s and splicing the coding portions ([[exon]]s) together.<ref name="pmid11343899">{{cite journal | vauthors = Will CL, Lührmann R | title = Spliceosomal UsnRNP biogenesis, structure and function | journal = Curr. Opin. Cell Biol. | volume = 13 | issue = 3 | pages = 290–301 | date = June 2001 | pmid = 11343899 | doi = 10.1016/S0955-0674(00)00211-8 | hdl = 11858/00-001M-0000-0012-F770-0 | hdl-access = free }}</ref> After a few more modifications, the spliced pre-mRNA becomes [[messenger RNA]] (mRNA) which is then exported from the nucleus and [[translation (biology)|translated]] into a protein by [[ribosomes]].
=== Discovery of proteins similar to the Sm proteins ===
The snRNA U6 (unlike U1, U2, U4 and U5) does not associate with the Sm proteins, even though the U6 snRNP is a central component in the [[spliceosome]]. In 1999 a protein heteromer was found that binds specifically to U6, and consisted of seven proteins clearly homologous to the Sm proteins.  These proteins were denoted LSm (like Sm) proteins ('''LSm1''', '''LSm2''', '''LSm3''', '''LSm4''', '''LSm5''', '''LSm6''' and '''LSm7'''), with the similar '''LSm8''' protein identified later.  In the bacterium ''[[Escherichia coli]]'', the Sm-like protein '''HF-I''' encoded by the gene '''''[[hfq]]''''' was described in 1968 as an essential '''h'''ost '''f'''actor for RNA [[bacteriophage]] '''Q'''β replication. The [[genome]] of ''[[Saccharomyces cerevisiae]]'' (Baker's Yeast) was sequenced in the mid-1990s, providing a rich resource for identifying [[Homology (biology)|homologs]] of these human proteins.  Subsequently, as more [[eukaryote]]s genomes were sequenced, it became clear that eukaryotes, in general, share homologs to the same set of seven Sm and eight LSm proteins.<ref name="pmid10801455">{{cite journal | vauthors = He W, Parker R | title = Functions of Lsm proteins in mRNA degradation and splicing | journal = Curr. Opin. Cell Biol. | volume = 12 | issue = 3 | pages = 346–50 | date = June 2000 | pmid = 10801455 | doi = 10.1016/S0955-0674(00)00098-3 }}</ref> Soon after, proteins homologous to these eukaryote LSm proteins were found in [[Archaea]] ('''Sm1''' and '''Sm2''') and [[Bacteria]] ('''Hfq''' and '''YlxS''' homologs).<ref name="pmid11331594">{{cite journal | vauthors = Törö I, Thore S, Mayer C, Basquin J, Séraphin B, Suck D | title = RNA binding in an Sm core domain: X-ray structure and functional analysis of an archaeal Sm protein complex | journal = EMBO J. | volume = 20 | issue = 9 | pages = 2293–303 | date = May 2001 | pmid = 11331594 | pmc = 125243 | doi = 10.1093/emboj/20.9.2293 }}</ref> The archaeal LSm proteins are more similar to the eukaryote LSm proteins than either are to bacterial LSm proteins.  The LSm proteins described thus far were rather small proteins, varying from 76 [[amino acid]]s (8.7&nbsp;kD [[Molecular mass|molecular weight]]) for human SmG to 231 amino acids (29&nbsp;kD molecular weight) for human SmB.  But recently, larger proteins have been discovered that include a LSm [[structural domain]] in addition to other protein structural domains (such as '''LSm10''', '''LSm11''', '''LSm12''', '''LSm13''', '''LSm14''', '''LSm15''', '''LSm16''', '''ataxin-2''', as well as archaeal '''Sm3''').
=== Discovery of the LSm fold ===
Around 1995, comparisons between the various LSm [[Homology (biology)|homologs]] identified two [[sequence motif]]s, 32 nucleic acids long (14 amino acids), that were very similar in each LSm homolog, and were separated by a non-conserved region of variable length.  This indicated the importance of these two sequence motifs (named '''Sm1''' and '''Sm2'''), and suggested that all LSm protein genes evolved from a single ancestral gene.<ref name="pmid7744013">{{cite journal | vauthors = Hermann H, Fabrizio P, Raker VA, Foulaki K, Hornig H, Brahms H, Lührmann R | title = snRNP Sm proteins share two evolutionarily conserved sequence motifs which are involved in Sm protein-protein interactions | journal = EMBO J. | volume = 14 | issue = 9 | pages = 2076–88 | date = May 1995 | pmid = 7744013 | pmc = 398308 | doi =  10.1002/j.1460-2075.1995.tb07199.x}}</ref> In 1999, crystals of [[Recombinant DNA|recombinant]] Sm proteins were prepared, allowing [[X-ray crystallography]] and determination of their atomic structure in three dimensions.<ref name="pmid10025403">{{cite journal | vauthors = Kambach C, Walke S, Young R, Avis JM, de la Fortelle E, Raker VA, Lührmann R, Li J, Nagai K | title = Crystal structures of two Sm protein complexes and their implications for the assembly of the spliceosomal snRNPs | journal = Cell | volume = 96 | issue = 3 | pages = 375–87 | date = February 1999 | pmid = 10025403 | doi = 10.1016/S0092-8674(00)80550-4 | s2cid = 17379935 | doi-access = free }}</ref> This demonstrated that the LSm proteins share a similar three-dimensional [[Structural domain|fold]] of a short [[alpha helix]] and a five-stranded folded [[beta sheet]], subsequently named the '''LSm fold'''.  Other investigations found that LSm proteins assemble into a [[torus]] (doughnut-shaped ring) of six or seven LSm proteins, and that RNA binds to the inside of the torus, with one [[nucleotide]] bound to each LSm protein.
== Structure ==
[[File:LSm Secondary Structure.JPG|thumb|400px|LSm secondary structure showing the N-terminal alpha helix and the five-strand antiparallel beta sheet]][[File:1B34 SmD1 8strand.JPG|thumb|400px|The LSm protein Human SmD1 showing the eight-strand beta sandwich peptide backbone description. (The beta sheet fold hinge runs along the bottom of the image.)]] Uridine phosphate binds in archaeal Sm1 between the β2b/β3a loop and β4b/β5 loop.  The [[uracil]] is stacked between the [[histidine]] and [[arginine]] residues, stabilized by [[hydrogen bond]]ing to an [[asparagine]] residue, and [[hydrogen bond]]ing between the [[aspartic acid|aspartate]] residue and the [[ribose]].  LSm proteins are characterized by a [[beta sheet]] (the [[secondary structure]]), folded into the LSm fold (the [[tertiary structure]]), polymerization into a six or seven member [[torus]] (the [[quaternary structure]]), and binding to [[RNA]] [[oligonucleotides]].<ref>[https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=structure&cmd=search&term= National Center for Biotechnology Information Structure Database PDB codes 1B34, 1D3B, 1I5L, 1KQ2, 1N9S, 1IB8.]</ref>  A modern paradigm classifies proteins on the basis of [[protein structure]] and is a currently active field, with three major approaches, [[Structural Classification of Proteins|SCOP]] ('''S'''tructural '''C'''lassification '''o'''f '''P'''roteins), [[CATH]] ('''C'''lass, '''A'''rchitecture, '''T'''opology, '''H'''omologous superfamily), and [[Families of structurally similar proteins|FSSP/DALI]] ('''F'''amilies of '''S'''tructurally '''S'''imilar '''P'''roteins).
=== Secondary ===
The [[secondary structure]] of a LSm protein is a small five-strand anti-parallel [[beta sheet]], with the strands identified from the [[N-terminal end]] to the [[C-terminal end]] as β1, β2, β3, β4, β5. The SCOP class of '''[[All-β proteins|All beta proteins]]''' and the CATH class of '''Mainly Beta''' are defined as protein structures that are primarily beta sheets, thus including LSm.  The SM1 [[sequence motif]] corresponds to the β1, β2, β3 strands, and the SM2 sequence motif corresponds to the β4 and β5 strands.  The first four beta strands are adjacent to each other, but β5 is adjacent to β1, turning the overall structure into a short barrel.  This structural topology is described as 51234.  A short (two to four turns) N-terminal [[alpha helix]] is also present in most LSm proteins.  The β3 and β4 strands are short in some LSm proteins, and are separated by an unstructured coil of variable length.  The β2, β3 and β4 strands are strongly bent about 120° degrees at their midpoints  The bends in these strands are often [[glycine]], and the side chains internal to the beta barrel are often the hydrophobic residues [[valine]], [[leucine]], [[isoleucine]] and [[methionine]].
=== Tertiary ===
SCOP simply classifies the LSm structure as the '''Sm-like fold''', one of 149 different Beta Protein folds, without any intermediate groupings.  The LSm beta sheet is sharply bent and described as a '''Roll''' architecture in CATH (one of 20 different beta protein architectures in CATH).  One of the beta strands (β5 in LSm) crosses the open edge of the roll to form a small '''SH3 type barrel''' topology (one of 33 beta roll topologies in CATH).  CATH lists 23 homologous superfamilies with an SH3 type barrel topology, one of which is the LSm structure ('''RNA Binding Protein''' in the CATH system).  SCOP continues its structural classification after Fold to Superfamily, Family and Domain, while CATH continues to Sequence Family, but these divisions are more appropriately described in the "Evolution and phylogeny" section.
The SH3-type barrel [[tertiary structure]] of the LSm fold is formed by the strongly bent (about 120°) β2, β3 and β4 strands, with the barrel structure closed by the β5 strand.  Emphasizing the tertiary structure, each bent beta strand can be described as two shorter beta strands.  The LSm fold can be viewed as an '''eight-strand anti-parallel beta sandwich''', with five strands in one plane and three strands in a parallel plane with about a 45° pitch angle between the two halves of the beta sandwich.  The short (two to four turns) N-terminal [[alpha helix]] occurs at one edge of the beta sandwich.  This alpha helix and the beta strands can be labeled (from the [[N-terminal end|N-terminus]] to the [[C-terminal end|C-terminus]]) α, β1, β2a, β2b, β3a, β3b, β4a, β4b, β5 where the a and b refer to either the two halves of a bent strand in the five-strand description, or to the individual strands in the eight-strand description.  Each strand (in the eight-strand description) is formed from five [[amino acid]] residues. Including the bends and loops between the strands, and the alpha helix, about 60 amino acid residues contribute to the LSm fold, but this varies between [[Homology (biology)|homologs]] due to variation in inter-strand loops, the alpha helix, and even the lengths of β3b and β4a strands.
=== Quaternary ===
LSm proteins typically assemble into a '''LSm ring''', a six or seven member [[torus]], about 7&nbsp;[[Metre|nanometers]] in diameter with a 2&nbsp;nanometer hole.  The ancestral condition is a [[Quaternary structure|homohexamer]] or [[Quaternary structure|homoheptamer]] of identical LSm subunits.  LSm proteins in [[eukaryote]]s form [[Quaternary structure|heteroheptamers]] of seven different LSm subunits, such as the Sm proteins.  Binding between the LSm proteins is best understood with the eight-strand description of the LSm fold.  The five-strand half of the beta sandwich of one subunit aligns with the three-strand half of the beta sandwich of the adjacent subunit, forming a twisted 8-strand beta sheet Aβ4a/Aβ3b/Aβ2a/Aβ1/Aβ5/Bβ4b/Bβ3a/Bβ2b, where the A and B refer to the two different subunits.  In addition to [[hydrogen bond]]ing between the Aβ5 and Bβ4b beta strands of the two LSm protein subunits, there are energetically favorable contacts between [[Hydrophobic effect|hydrophobic]] amino acid side chains in the interior of the contact area, and energetically favorable contacts between [[Hydrophile|hydrophilic]] amino acid side chains around the periphery of the contact area.
=== RNA oligonucleotide binding ===
LSm rings form [[ribonucleoprotein]] complexes with [[RNA]] [[oligonucleotide]]s that vary in binding strength from very stable complexes (such as the Sm class snRNPs) to transient complexes.  RNA oligonucleotides generally bind inside the hole (lumen) of the LSm torus, one [[nucleotide]] per LSm subunit, but additional nucleotide binding sites have been reported at the top ([[Alpha helix|α helix]] side) of the ring.  The exact chemical nature of this binding varies, but common motifs include stacking the heterocyclic base (often [[uracil]]) between planar side chains of two amino acids, [[hydrogen bond]]ing to the heterocyclic base and/or the [[ribose]], and [[Salt bridge (protein)|salt bridges]] to the [[phosphate]] group.
== Functions ==
The various kinds of LSm rings function as scaffolds or [[chaperone (protein)|chaperone]]s for [[RNA]] [[oligonucleotide]]s, assisting the RNA to assume and maintain the proper three-dimensional structure.  In some cases, this allows the oligonucleotide RNA to function catalytically as a [[ribozyme]].  In other cases, this facilitates modification or degradation of the RNA, or the assembly, storage, and intracellular transport of [[ribonucleoprotein]] complexes.<ref name="pmid16051491">{{cite journal | vauthors = Khusial P, Plaag R, Zieve GW | title = LSm proteins form heptameric rings that bind to RNA via repeating motifs | journal = Trends Biochem. Sci. | volume = 30 | issue = 9 | pages = 522–8 | date = September 2005 | pmid = 16051491 | doi = 10.1016/j.tibs.2005.07.006 }}</ref>
=== Sm ring ===
The '''Sm ring''' is found in the [[Cell nucleus|nucleus]] of all [[eukaryote]]s (about 2.5 × 10<sup>6</sup> copies per proliferating human cell), and has the best understood functions.  The Sm ring is a [[Quaternary structure|heteroheptamer]].  The Sm-class [[Non-coding RNA|snRNA]] molecule (in the 5' to 3' direction) enters the lumen (doughnut hole) at the SmE subunit and proceeds sequentially in a clockwise fashion (looking from the α helix side) inside the lumen (doughnut hole) to the SmG, SmD3, SmB, SmD1, SmD2 subunits, exiting at the SmF subunit.<ref name="pmid11226169">{{cite journal | vauthors = Urlaub H, Raker VA, Kostka S, Lührmann R | title = Sm protein-Sm site RNA interactions within the inner ring of the spliceosomal snRNP core structure | journal = EMBO J. | volume = 20 | issue = 1–2 | pages = 187–96 | date = January 2001 | pmid = 11226169 | pmc = 140196 | doi = 10.1093/emboj/20.1.187 }}</ref> (SmB can be replaced by the splice variant SmB' and by SmN in neural tissues.)  The Sm ring permanently binds to the U1, U2, U4 and U5 snRNAs which form four of the five [[snRNP]]s that constitute the major [[spliceosome]].  The Sm ring also permanently binds to the '''[[U11 snRNA|U11]]''', '''[[U12 snRNA|U12]]''' and '''[[U4atac minor spliceosomal RNA|U4atac]]''' snRNAs which form four of the five snRNPs (including the U5 snRNP) that constitute the [[minor spliceosome]].  Both of these spliceosomes are central RNA-processing complexes in the maturation of [[messenger RNA]] from [[precursor mRNA|pre-mRNA]].  Sm proteins have also been reported to be part of [[ribonucleoprotein]] component of [[telomerase]].<ref name="pmid10490028">{{cite journal | vauthors = Seto AG, Zaug AJ, Sobel SG, Wolin SL, Cech TR | title = Saccharomyces cerevisiae telomerase is an Sm small nuclear ribonucleoprotein particle | journal = Nature | volume = 401 | issue = 6749 | pages = 177–80 | date = September 1999 | pmid = 10490028 | doi = 10.1038/43694 | bibcode = 1999Natur.401..177S | s2cid = 4414530 }}</ref>
=== Lsm2-8 ring ===
The two Lsm2-8 snRNPs (U6 and '''[[U6atac minor spliceosomal RNA|U6atac]]''') have the key catalytic function in the major and minor spliceosomes.  These snRNPs do not include the Sm ring, but instead use the [[Quaternary structure|heteroheptameric]] '''Lsm2-8 ring'''.  The LSm rings are about 20 times less abundant than the Sm rings.  The order of these seven LSm proteins in this ring is not known, but based on [[Homology (biology)|amino acid sequence homology]] with the Sm proteins, it is speculated that the snRNA (in the 5' to 3' direction) may bind first to LSm5, and precedes sequentially clockwise to the LSm7, LSm4, LSm8, LSm2, LSm3, and exiting at the LSm6 subunit.  Experiments with ''[[Saccharomyces cerevisiae]]'' (budding yeast) mutations suggest that the Lsm2-8 ring assists the reassociation of the U4 and U6 snRNPs into the '''U4/U6 di-snRNP'''.<ref name="pmid15916535">{{cite journal | vauthors = Beggs JD | title = Lsm proteins and RNA processing | journal = Biochem. Soc. Trans. | volume = 33 | issue = Pt 3 | pages = 433–8 | date = June 2005 | pmid = 15916535 | doi = 10.1042/BST0330433 }}</ref>  (After completion of exon deletion and intron splicing, these two snRNPs must reassociate for the spliceosome to initiate another exon/intron splicing cycle.  In this role, the Lsm2-8 ring acts as an RNA [[chaperone (protein)|chaperone]] instead of an RNA scaffold.)  The Lsm2-8 ring also forms an snRNP with the '''U8''' [[Non-coding RNA|small nucleolar RNA]] (snoRNA) which localizes in the [[nucleolus]].  This ribonucleoprotein complex is necessary for processing [[ribosomal RNA]] and [[transfer RNA]] to their mature forms.<ref name="pmid12438310">{{cite journal | vauthors = Kufel J, Allmang C, Petfalski E, Beggs J, Tollervey D | title = Lsm Proteins are required for normal processing and stability of ribosomal RNAs | journal = J. Biol. Chem. | volume = 278 | issue = 4 | pages = 2147–56 | date = January 2003 | pmid = 12438310 | doi = 10.1074/jbc.M208856200 | doi-access = free }}</ref> The Lsm2-8 ring is reported to have a role in the processing of pre-P RNA into [[RNase P|RNase P RNA]].  In contrast to the Sm ring, the Lsm2-8 ring does not permanently bind to its snRNA and snoRNA.
=== Sm10/Sm11 ring ===
A second type of Sm ring exists where [[LSM10|LSm10]] replaces SmD1 and LSm11 replaces SmD2.  LSm11 is a two domain protein with the [[C-terminal end|C-terminal]] domain being a LSm domain.  This heteroheptamer ring binds with the U7 snRNA in the '''U7 snRNP'''.  The U7 snRNP mediates processing of the [[Histone 3' UTR stem-loop|3' UTR stem-loop]] of the [[histone]] [[messenger RNA|mRNA]] in the nucleus.<ref name="pmid15526162">{{cite journal | vauthors = Schümperli D, Pillai RS | title = The special Sm core structure of the U7 snRNP: far-reaching significance of a small nuclear ribonucleoprotein | journal = Cell. Mol. Life Sci. | volume = 61 | issue = 19–20 | pages = 2560–70 | date = October 2004 | pmid = 15526162 | doi = 10.1007/s00018-004-4190-0 | s2cid = 5780814 | url = http://doc.rero.ch/record/311624/files/18_2004_Article_4190.pdf }}</ref> Like the Sm ring, it is assembled in the cytoplasm onto the U7 snRNA by a specialized SMN complex.
=== Lsm1-7 ring ===
A second type of Lsm ring is the '''Lsm1-7 ring''', which has the same structure as the Lsm2-8 ring except that LSm1 replaces LSm8.  In contrast to the Lsm2-8 ring, the Lsm1-7 ring localizes in the [[cytoplasm]] where it assists in degrading [[messenger RNA]] in [[ribonucleoprotein]] complexes.  This process controls the turnover of messenger RNA so that ribosomal [[translation (biology)|translation]] of mRNA to protein responds quickly to changes in [[transcription (genetics)|transcription]] of DNA to messenger RNA by the cell. LSM1-7, together with [[Decapping complex#Pat1|Pat1]], has been shown to play a role in the formation of [[P-bodies]] after deadenylation.<ref>{{Cite journal |last1=Decker |first1=C. J. |last2=Parker |first2=R. |date=2012-07-03 |title=P-Bodies and Stress Granules: Possible Roles in the Control of Translation and mRNA Degradation |url=http://dx.doi.org/10.1101/cshperspect.a012286 |journal=Cold Spring Harbor Perspectives in Biology |volume=4 |issue=9 |pages=a012286 |doi=10.1101/cshperspect.a012286 |pmid=22763747 |pmc=3428773 |issn=1943-0264}}</ref>
=== Gemin6 and Gemin7 ===
{{See also|SnRNP#Assembly of core snRNPs in the SMN complex}}
The '''SMN complex''' (described under "Biogenesis of snRNPs") is composed of the SMN protein and '''Gemin2-8'''.  Two of these, '''Gemin 6''' and '''Gemin7''' have been discovered to have the LSm structure, and to form a heterodimer. These may have a [[chaperone (protein)|chaperone]] function in the SMN complex to assist the formation of the Sm ring on the Sm-class [[Non-coding RNA|snRNAs]].<ref name="pmid15939020">{{cite journal | vauthors = Ma Y, Dostie J, Dreyfuss G, Van Duyne GD | title = The Gemin6-Gemin7 heterodimer from the survival of motor neurons complex has an Sm protein-like structure | journal = Structure | volume = 13 | issue = 6 | pages = 883–92 | date = June 2005 | pmid = 15939020 | doi = 10.1016/j.str.2005.03.014 | doi-access = free }}</ref> '''PRMT5 complex''' is composed of [[Protein arginine methyltransferase 5|PRMT5]], [[CLNS1A|pICln]], [[WD repeat-containing protein 77|WD45 (Mep50)]]. pICln helps to form Sm opened ring on SMN complex. SMN complex assists in the assembly of [[snRNP]]s where the Sm ring is in the open conformation on SMN complex and this Sm ring is loaded onto the [[snRNA]] by SMN complex.<ref>
{{cite journal | vauthors = Chari A, Golas MM, Klingenhäger M, Neuenkirchen N, Sander B, Englbrecht C, Sickmann A, Stark H, Fischer U | title = An Assembly Chaperone Collaborates with the SMN Complex to Generate Spliceosomal SnRNPs | journal = Cell | volume = 135 | issue = 3 | pages = 497–509 | date = 2008-10-31 | pmid = 18984161 | doi = 10.1016/j.cell.2008.09.020 | hdl = 11858/00-001M-0000-0010-93A3-A | s2cid = 119444 | hdl-access = free }}</ref>
=== LSm12-16 and other multi-domain LSm proteins ===
The '''LSm12-16''' proteins have been described very recently.  These are two-domain proteins with a [[N-terminal end|N-terminal]] LSm domain and a [[C-terminal end|C-terminal]] methyl transferase domain.<ref name="pmid15225602">{{cite journal | vauthors = Albrecht M, Lengauer T | title = Novel Sm-like proteins with long C-terminal tails and associated methyltransferases | journal = FEBS Lett. | volume = 569 | issue = 1–3 | pages = 18–26 | date = July 2004 | pmid = 15225602 | doi = 10.1016/j.febslet.2004.03.126 | s2cid = 37187215 | doi-access = free }}</ref> Very little is known about the function of these proteins, but presumably they are member of LSm-domain rings that interact with RNA.  There is some evidence that LSm12 is possibly involved in mRNA degradation and LSm13-16 may have roles in regulation of [[mitosis]].  Unexpectedly, LSm12 was recently implicated in [[calcium signaling]] by acting as the intermediate binding-protein for the nucleotide second messenger, NAADP ([[nicotinic acid adenine dinucleotide phosphate]]) that activates endo-lysosomal Ca<sup>2+</sup> channels TPCs ([[two-pore channel]]s).<ref name=":0">{{Cite journal|last1=Zhang|first1=Jiyuan|last2=Guan|first2=Xin|last3=Shah|first3=Kunal|last4=Yan|first4=Jiusheng|date=2021-08-06|title=Lsm12 is an NAADP receptor and a two-pore channel regulatory protein required for calcium mobilization from acidic organelles|journal=Nature Communications|volume=12|issue=1|pages=4739|doi=10.1038/s41467-021-24735-z|issn=2041-1723|pmc=8346516|pmid=34362892|bibcode=2021NatCo..12.4739Z }}</ref> This occurred by NAADP binding to the LSm domain, not the AD domain.<ref name=":0" /> A large protein of unknown function, '''ataxin-2''', associated with the neurodegenerative disease [[spinocerebellar ataxia|spinocerebellar ataxia type 2]], also has a N-terminal LSm domain.
=== Archaeal Sm rings ===
Two LSm proteins are found in a second [[Domain (biology)|domain]] of life, the [[Archaea]].  These are the '''Sm1''' and '''Sm2''' proteins (not to be confused with the Sm1 and Sm2 [[sequence motif]]s), and are sometimes identified as '''S'''m-like '''a'''rchaeal '''p'''roteins '''SmAP1''' and '''SmAP2''' for this reason.<ref name="pmid12649441">{{cite journal | vauthors = Mura C, Kozhukhovsky A, Gingery M, Phillips M, Eisenberg D | title = The oligomerization and ligand-binding properties of Sm-like archaeal proteins (SmAPs) | journal = Protein Sci. | volume = 12 | issue = 4 | pages = 832–47 | date = April 2003 | pmid = 12649441 | pmc = 2323858 | doi = 10.1110/ps.0224703 }}</ref> Sm1 and Sm2 generally form [[Quaternary structure|homoheptamer]] rings, although homohexamer rings have been observed.  Sm1 rings are similar to [[eukaryote]] Lsm rings in that they form in the absence of RNA while Sm2 rings are similar to eukaryote Sm rings in that they require [[uridine]]-rich RNA for their formation.  They have been reported to associate with [[RNase P|RNase P RNA]], suggesting a role in [[transfer RNA]] processing, but their function in archaea in this process (and possibly processing other RNA such as [[ribosomal RNA]]) is mostly unknown.  One of the two main branches of archaea, the [[Thermoproteota|crenarchaeotes]] have a third known type of archaeal LSm protein, '''Sm3'''.  This is a two-domain protein with a [[N-terminal end|N-terminal]] LSm domain that forms a [[Quaternary structure|homoheptamer]] ring.  Nothing is known about the function of this LSm protein, but presumably it interacts with, and probably helps process, RNA in these organisms.
=== Bacterial LSm rings ===
Several LSm proteins have been reported in the third [[Domain (biology)|domain]] of life, the [[Bacteria]].  '''Hfq''' protein forms [[Quaternary structure|homohexamer]] rings, and was originally discovered as necessary for infection by the [[bacteriophage Qβ]], although this is clearly not the native function of this protein in bacteria.  It is not universally present in all bacteria, but has been found in [[Pseudomonadota]], [[Bacillota]], [[Spirochaetota]], [[Thermotogota]], [[Aquificota]], and one species of [[Archaea]].  (This last instance is probably a case of [[horizontal gene transfer]].)  Hfq is [[Pleiotropy|pleiotropic]] with a variety of interactions, generally associated with [[Translation (biology)|translation]] regulation.  These include blocking ribosome binding to [[messenger RNA|mRNA]], marking mRNA for degradation by binding to their [[Polyadenylation|poly-A tails]], and association with bacterial small regulatory RNAs (such as DsrA RNA) that control translation by binding to certain mRNAs.<ref name="pmid12093755">{{cite journal | vauthors = Schumacher MA, Pearson RF, Møller T, Valentin-Hansen P, Brennan RG | title = Structures of the pleiotropic translational regulator Hfq and an Hfq-RNA complex: a bacterial Sm-like protein | journal = EMBO J. | volume = 21 | issue = 13 | pages = 3546–56 | date = July 2002 | pmid = 12093755 | pmc = 126077 | doi = 10.1093/emboj/cdf322 }}</ref><ref name="pmid15561140">{{cite journal | vauthors = Lease RA, Woodson SA | title = Cycling of the Sm-like protein Hfq on the DsrA small regulatory RNA | journal = J. Mol. Biol. | volume = 344 | issue = 5 | pages = 1211–23 | date = December 2004 | pmid = 15561140 | doi = 10.1016/j.jmb.2004.10.006 }}</ref> A second bacterial LSm protein is '''YlxS''' (sometimes also called YhbC), which was first identified in the soil bacterium ''[[Bacillus subtilis]]''.  This is a two-domain protein with a [[N-terminal end|N-terminal]] LSm domain.  Its function is unknown, but [[Homology (biology)|amino acid sequence homologs]] are found in virtually every bacterial [[genome]] to date, and it may be an essential protein.<ref name="pmid11493012">{{cite journal | vauthors = Yu L, Gunasekera AH, Mack J, Olejniczak ET, Chovan LE, Ruan X, Towne DL, Lerner CG, Fesik SW | title = Solution structure and function of a conserved protein SP14.3 encoded by an essential Streptococcus pneumoniae gene | journal = J. Mol. Biol. | volume = 311 | issue = 3 | pages = 593–604 | date = August 2001 | pmid = 11493012 | doi = 10.1006/jmbi.2001.4894 }}</ref> The middle domain of the small conductance mechanosensitive channel '''MscS''' in ''[[Escherichia coli]]'' forms a homoheptameric ring.<ref name="pmid12446901">{{cite journal | vauthors = Bass RB, Strop P, Barclay M, Rees DC | title = Crystal structure of Escherichia coli MscS, a voltage-modulated and mechanosensitive channel | journal = Science | volume = 298 | issue = 5598 | pages = 1582–7 | date = November 2002 | pmid = 12446901 | doi = 10.1126/science.1077945 | bibcode = 2002Sci...298.1582B | s2cid = 15945269 | url = https://authors.library.caltech.edu/51677/7/BassSOM.pdf }}</ref> This LSm domain has no apparent RNA-binding function, but the homoheptameric torus is part of the central channel of this membrane protein.
== Evolution and phylogeny ==
LSm [[Homology (biology)|homologs]] are found in all three [[Domain (biology)|domains]] of life, and may even be found in every single [[organism]]. [[Computational phylogenetics|Computational phylogenetic]] methods are used to infer [[Phylogenetics|phylogenetic]] relations. [[Sequence alignment]] between the various LSm homologs are the appropriate tool for this, such as [[multiple sequence alignment]] of the primary structure (amino acid sequence), and [[structural alignment]] of the tertiary structure (three-dimensional structure). It is hypothesized that a gene for a LSm protein was present in the [[last universal ancestor]] of all life.<ref name="pmid11259661">{{cite journal | vauthors = Achsel T, Stark H, Lührmann R | title = The Sm domain is an ancient RNA-binding motif with oligo(U) specificity | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 7 | pages = 3685–9 | date = March 2001 | pmid = 11259661 | pmc = 31112 | doi = 10.1073/pnas.071033998 | bibcode = 2001PNAS...98.3685A | doi-access = free }}</ref> Based on the functions of known LSm proteins, this original LSm protein may have assisted [[ribozyme]]s in the processing of RNA for synthesizing proteins as part of the [[RNA world hypothesis]] of early life.  According to this view, this gene was passed from ancestor to descendant, with frequent [[mutation]]s, [[gene duplication]]s and occasional [[horizontal gene transfer]]s. In principle, this process can be summarized in a [[phylogenetic tree]] with the root in the last universal ancestor (or earlier), and with the tips representing the universe of LSm genes existing today.
=== Homomeric LSm rings in bacteria and archaea ===
Based on structure, the known LSm proteins divide into a group consisting of the bacterial LSm proteins (Hfq, YlxS and MscS) and a second group of all other LSm proteins, in accordance with the most recently published [[phylogenetic tree]]s.<ref name="pmid16513982">{{cite journal | vauthors = Ciccarelli FD, Doerks T, von Mering C, Creevey CJ, Snel B, Bork P | title = Toward automatic reconstruction of a highly resolved tree of life | journal = Science | volume = 311 | issue = 5765 | pages = 1283–7 | date = March 2006 | pmid = 16513982 | doi = 10.1126/science.1123061 | bibcode = 2006Sci...311.1283C | citeseerx = 10.1.1.381.9514 | s2cid = 1615592 }}</ref> The three archaeal LSm proteins (Sm1, Sm2 and Sm3) also cluster as a group, distinct from the eukaryote LSm proteins.  Both the bacterial and archaeal LSm proteins polymerize to homomeric rings, which is the ancestral condition.
=== Heteromeric LSm rings in eukaryotes ===
A series of gene duplications of a single eukaryote LSm gene resulted in most (if not all) of the known eukaryote LSm genes.  Each of the seven Sm proteins has greater [[Homology (biology)|amino acid sequence homology]] to a corresponding Lsm protein than to the other Sm proteins.  This suggests that an ancestral LSm gene duplicated several times, resulting in seven [[Homology (biology)|paralogs]].  These subsequently diverged from each other so that the ancestral homoheptamer LSm ring became a heteroheptamer ring.  Based on the known functions of LSm proteins in eukaryotes and archaea, the ancestral function may have been processing of pre-[[ribosomal RNA]], pre-[[transfer RNA]], and pre-[[RNase P]].  Then, according to this hypothesis, the seven ancestral eukaryote LSm genes duplicated again to seven pairs of Sm/LSm paralogs; LSm1/SmB, LSm2/SmD1, LSm3/SmD2, LSm4/SmD3, LSm5/SmE, LSm6/SmF and LSm7/SmG.  These two group of seven LSm genes (and the corresponding two kinds of LSm rings) evolved to an Sm ring (requiring RNA) and a Lsm ring (which forms without RNA).  The LSm1/LSm8 paralog pair also seems to have originated prior to the last common eukaryote ancestor, for a total of at least 15 LSm protein genes.  The SmD1/LSm10 paralog pair and the SmD2/LSm11 paralog pair exist only in [[animal]]s, [[Fungus|fungi]], and the [[amoebozoa]] (sometimes identified as the [[unikont]] clade) and appears to be absent in the [[bikont]] clade ([[chromalveolate]]s, [[Excavata|excavate]]s, [[plant]]s and [[rhizaria]]).  Therefore, these two gene duplications predated this fundamental split in the eukaryote lineage.  The SmB/SmN paralog pair is seen only in the [[Eutheria|placental mammals]], which dates this LSm gene duplication.
== Biogenesis of snRNPs ==
{{main|snRNP}}
Small nuclear ribonucleoproteins (snRNPs) assemble in a tightly orchestrated and regulated process that involves both the [[cell nucleus]] and [[cytoplasm]].<ref name="pmid15564372">{{cite journal | vauthors = Kiss T | title = Biogenesis of small nuclear RNPs | journal = J. Cell Sci. | volume = 117 | issue = Pt 25 | pages = 5949–51 | date = December 2004 | pmid = 15564372 | doi = 10.1242/jcs.01487 | s2cid = 10316639 | doi-access =  }}</ref>
== References ==
{{reflist|2}}
== External links ==
* [https://www.ebi.ac.uk/interpro/entry/pfam/PF01423/ InterPro LSm entry]
{{Autoantibodies}}
{{DEFAULTSORT:Lsm}}
[[Category:Protein families]]
[[Category:Spliceosome]]