LSm

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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
LSM domain
SCOP2
1d3b / SCOPe / SUPFAM
CDDcd00600
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

In

mRNA
processing and regulation.

The Sm proteins were first discovered as

systemic lupus erythematosus (SLE), a debilitating autoimmune disease. They were named Sm proteins in honor of Stephanie Smith, a patient who suffered from SLE.[1]
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

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 proteins begins with a young woman, Stephanie Smith, who was diagnosed in 1959 with systemic lupus erythematosus (SLE), eventually succumbing to complications of the disease in 1969 at the age of 22.[1] 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 autoimmune disease, SLE patients produce antibodies to antigens in their cells' nuclei, most frequently to their own DNA. However, Kunkel and Tan found in 1966 that Smith produced antibodies to a set of nuclear proteins, which they named the 'smith antigen' (Sm Ag).[2] 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 (

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

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

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

FSSP/DALI
(Families of Structurally Similar Proteins).

Secondary

The

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

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 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

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 bonding between the Aβ5 and Bβ4b beta strands of the two LSm protein subunits, there are energetically favorable contacts between hydrophobic amino acid side chains in the interior of the contact area, and energetically favorable contacts between hydrophilic
amino acid side chains around the periphery of the contact area.

RNA oligonucleotide binding

LSm rings form

group.

Functions

The various kinds of LSm rings function as scaffolds or

Sm ring

The Sm ring is found in the

Lsm2-8 ring

The two Lsm2-8 snRNPs (U6 and

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

3' UTR stem-loop of the histone mRNA in the nucleus.[14]
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

transcription of DNA to messenger RNA by the cell. LSM1-7, together with Pat1, has been shown to play a role in the formation of P-bodies after deadenylation.[15]

Gemin6 and Gemin7

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

snRNA by SMN complex.[17]

LSm12-16 and other multi-domain LSm proteins

The LSm12-16 proteins have been described very recently. These are two-domain proteins with a

C-terminal methyl transferase domain.[18] 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 Ca2+ channels TPCs (two-pore channels).[19] This occurred by NAADP binding to the LSm domain, not the AD domain.[19] A large protein of unknown function, ataxin-2, associated with the neurodegenerative disease spinocerebellar ataxia type 2
, also has a N-terminal LSm domain.

Archaeal Sm rings

Two LSm proteins are found in a second

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

N-terminal LSm domain. Its function is unknown, but amino acid sequence homologs are found in virtually every bacterial genome to date, and it may be an essential protein.[23] The middle domain of the small conductance mechanosensitive channel MscS in Escherichia coli forms a homoheptameric ring.[24]
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

RNA world hypothesis of early life. According to this view, this gene was passed from ancestor to descendant, with frequent mutations, gene duplications and occasional horizontal gene transfers. 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 trees.[26] 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

chromalveolates, excavates, plants 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 placental mammals
, which dates this LSm gene duplication.

Biogenesis of snRNPs

Small nuclear ribonucleoproteins (snRNPs) assemble in a tightly orchestrated and regulated process that involves both the cell nucleus and cytoplasm.[27]

References

External links

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