Since 1995, when mutations in SMN were shown to
cause spinal muscular atrophy,2there has been great
progress toward understanding the molecular functions of
the SMN protein in cells, the cellular pathways that are
affected by decreased expression of SMN, and the design of
potential therapeutic strategies to treat patients with this dis-
ease. Several recent reviews have discussed SMN function.1,3-6
Here we focus on the function of SMN in spliceosomal
ribonucleoprotein biogenesis and on how defects in this
function may result in spinal muscular atrophy.
The SMN Complex
The SMN protein is a 294–amino acid polypeptide that is
expressed in all metazoans and in all cell types of vertebrate
organisms. Biochemically, SMN does not appear to exist
within cells in isolation but instead forms part of a large
protein complex, the SMN complex. The SMN complex is
composed of the SMN protein and 7 additional proteins,
Gemin2-8.7-14The Gemins bind to and colocalize with SMN
in the cytoplasm and in discrete nuclear bodies called
gems.11The SMN protein is an essential protein in all cell
types studied thus far. Complete knockout of SMN results
in embryonic lethality in divergent organisms, including
human, mouse, chicken, and Caenorhabditis elegans and is
also lethal in Schizosaccharomyces pombe. In experimental
systems, SMN expression appears necessary for cell survival
regardless of cell type; therefore, a major mystery of the
pathogenesis in spinal muscular atrophy is the basis of motor
neuron–specific cell loss with relative depletion of SMN
throughout the body.
atrophy. Within the pediatric population, spinal muscular
atrophy can be included in the list of single gene defect
diseases where the loss of a single essential protein
expressed in all tissues and cells results in the selective
death of a single cell type. In the case of spinal muscular
atrophy, this is the lower motor neuron. As has been
noted elsewhere, another example of this type of disease
is Rett syndrome, which results from mutations in a tran-
scriptional repressor that is also ubiquitously expressed.1
Like Rett syndrome, the basis of cell selectivity in spinal
muscular atrophy is not clear. Spinal muscular atrophy
also shares similarities (and, consequently, pathogenic
riddles) with several adult neurodegenerative disorders that
affect motor neurons, including amyotrophic lateral sclero-
sis, primary lateral sclerosis, hereditary spastic parapareses,
and the distal hereditary neuropathies. Thus, lessons from
the study of the molecular pathogenesis of spinal muscular
atrophy may provide important insights into other neuroge-
utations in the survival motor neuron gene
(SMN) that decrease expression of the func-
tional SMN protein result in spinal muscular
Special Issue Article
Molecular Functions of the SMN Complex
Stephen J. Kolb, MD, PhD, Daniel J. Battle, PhD, and Gideon Dreyfuss, PhD
The SMN complex is essential for the biogenesis of spliceoso-
mal small nuclear ribonucleoproteins and likely functions in
the assembly, metabolism, and transport of a diverse number
of other ribonucleoproteins. Specifically, the SMN complex
assembles 7 Sm proteins into a core structure around a highly
conserved sequence of ribonucleic acid (RNA) found in small
nuclear RNAs. The complex recognizes specific sequences and
structural features of small nuclear RNAs and Sm proteins
and assembles small nuclear ribonucleoproteins in a stepwise
fashion. In addition to the SMN protein, the SMN complex
contains 7 additional proteins known as Gemin2-8, each likely
to play a role in ribonucleoprotein biogenesis. This review
focuses on the current understanding of the mechanism of the
role of the SMN complex in small nuclear ribonucleoprotein
assembly and considers the relationship of this function to
spinal muscular atrophy.
Keywords: spinal muscular atrophy; ribonucleoproteins;
From the Howard Hughes Medical Institute and the Department of
Biochemistry and Biophysics, University of Pennsylvania School of
Address correspondence to: Gideon Dreyfuss, PhD, Department of
Biochemistry and Biophysics, University of Pennsylvania School of Medi-
cine, 330 Clinical Research Building, 415 Curie Boulevard, Philadelphia,
PA 19104-6148; e-mail: firstname.lastname@example.org.
Kolb SJ, Battle DJ, Dreyfuss G. Molecular functions of the SMN complex.
J Child Neurol. 2007;22:990-994.
Journal of Child Neurology
Volume 22 Number 8
August 2007 990-994
© 2007 Sage Publications
Molecular Functions of the SMN Complex / Kolb et al
The SMN complex is large (40S to 80S in sucrose gradi-
ent sedimentation) and is salt resistant (750-mmol/L NaCl)4;
however, under less stringent conditions, the SMN complex
is bound to several proteins, including the spliceosomal Sm
proteins.15,16Insights into the possible cellular functions of
the SMN complex have been derived from a detailed analy-
sis of the substrate proteins and small nuclear ribonucleic
acids (RNAs) that interact with the SMN complex.17,18The
function of the SMN complex in spliceosomal small nuclear
ribonucleoprotein assembly is discussed in detail later here
and serves as an example of SMN function; however,
the SMN complex likely also functions in the assembly,
metabolism, and transport of diverse classes of ribonucleo-
proteins, including small nucleolar ribonucleoproteins,
telomerase ribonucleoprotein, microribonucleoproteins, and
the machineries that carry out transcription and premessen-
ger RNA splicing.18-29
Spliceosomal U Small Nuclear
The premessenger RNA splicing process is essential for the
successful execution of eukaryotic gene expression and is
carried out by the spliceosome in the nucleus. The major
components of the spliceosome are the U1, U2, U5, and
U4/U6 small nuclear ribonucleoproteins.30Each of the
small nuclear ribonucleoproteins (except for U6) is com-
posed of 1 small nuclear RNA molecule, a set of 7 common
proteins, and several proteins specific to individual small
nuclear RNAs.30-32A crucial aspect of small nuclear ribonu-
cleoprotein biogenesis is that although assembly of these
components can occur spontaneously in vitro, within cells,
the process is highly regulated and requires both adenosine
triphosphate hydrolysis and dedicated assembly factors.15,33
Small nuclear ribonucleoprotein biogenesis begins with the
transcription of the U small nuclear RNAs in the nucleus,
followed by their export to the cytoplasm, where the major
assembly of the small nuclear ribonucleoproteins occurs.
The common proteins, called Sm proteins (B/B', D1, D2,
D3, E, F, and G), are arranged into a stable heptameric ring,
the Sm core, on a highly conserved, uridine-rich sequence
motif, the Sm site, of the small nuclear RNAs.34-36After
assembly, the 7-methyl guanosine cap of the small nuclear
RNA is modified into a 2,2,7-trimethyl guanosine cap, and
the properly assembled and modified small nuclear ribonu-
cleoproteins are then imported into the nucleus, where
additional small nuclear ribonucleoprotein-specific proteins
associate to form fully functional small nuclear ribonucleo-
proteins.30,37-41Mature small nuclear ribonucleoproteins
then carry out the process of premessenger RNA splicing.
Clearly, to ensure that splicing is carried out in an efficient
and timely manner, the process of small nuclear ribonucle-
oprotein assembly must run smoothly and efficiently.
How do cells ensure that Sm proteins will be assem-
bled only onto the correct small nuclear ribonucleopro-
tein? This is where the SMN complex is essential. The
SMN complex directly recognizes and binds to both the
protein and the RNA components of the ribonucleopro-
teins and facilitates their interaction, thereby ensuring a
strict specificity of the small nuclear ribonucleoprotein
assembly process (Figure 1).
To enforce specificity, the SMN complex must be able to
specifically bind to Sm proteins. In fact, each component of
the SMN complex, except Gemin2, binds directly to Sm pro-
teins. Gemin6 and Gemin7 were both recently shown to have
structures similar to Sm proteins, and reduction of Gemin6
by RNA interference disrupted the ability of the SMN com-
plex to bind Sm proteins. In addition, the SMN protein itself
binds to arginine- and glycine-rich domains found in the Sm
proteins B, D1, and D3. This interaction is enhanced by a
posttranslational, symmetric dimethyl arginine modification
that occurs at specific arginines in the glycine-rich domains
of the Sm proteins—a reaction carried out by the 20S methy-
losome that contains an arginine methyltransferase called
JBP1 or PRMT5.17Clearly, the SMN complex is a machine
designed to bind Sm proteins.
The SMN complex also binds directly and with sequence
specificity to the spliceosomal U small nuclear RNAs.16,42
The minimal SMN complex–binding domain in small nuclear
RNAs, except U1, is composed of an Sm site (AUUUUUG)
and an adjacent 3' stem loop (Figure 2). A detailed analysis
of this binding demonstrated that although the Sm site is
recognized by virtue of its sequence, the specific sequence of
the adjacent 3' stem loop is not important, provided that it is
located within a short distance of the 3' end of the RNA and
that the stem contains from 7 to 12 base pairs and the loop
contains 4 to 17 nucleotides.42These sequence and struc-
tural features appear to be uniquely present within U small
nuclear RNAs (interestingly, they are also present in the
small nuclear RNA encoded by the lymphotrophic
Herpesvirus saimiri43); therefore, the SMN complex scruti-
nizes RNAs that contain an Sm site, identifies the spliceoso-
mal small nuclear RNAs by recognizing the small nuclear
ribonucleoprotein code contained within them, and then
assembles Sm proteins onto them.
It is now apparent that the Gemins, not only the SMN
protein, are essential to the process of small nuclear
ribonucleoprotein assembly. Recently, Gemin5 was iden-
tified as the small nuclear RNA-binding protein of the
SMN complex.44Gemin5 directly and specifically binds
to the small nuclear ribonucleoprotein code at the 3' end
of small nuclear RNAs. By providing the SMN complex
with the ability to bind to this class of RNAs, Gemin5
serves to specify small nuclear RNAs, among all cellular
RNAs, for assembly into functional small nuclear ribonu-
cleoproteins. Gemin5 is a 175-kDa protein with no rec-
ognizable RNA-binding motif. Rather, the N-terminal half
Journal of Child Neurology / Vol. 22, No. 8, August 2007
of Gemin5 contains 13 WD repeats, whereas the C-terminal
half shows no homology with any other known proteins.
As such, Gemin5 seems to be unique among RNA-binding
The capacity of a cell to assemble small nuclear ribonu-
cleoproteins can now be measured quantitatively, and it
is proportional to the expression levels of the SMN protein
in the cell.45In cells expressing low levels of SMN, either
through mutation of SMN (ie, spinal muscular atrophy)
or through RNA interference in experimental systems,
small nuclear ribonucleoprotein assembly is correspond-
ingly decreased. The ability to measure small nuclear
ribonucleoprotein assembly capacity is not strictly a measure
of the expression of SMN because decreased assembly is also
seen in cells depleted of other Gemins. In experimental sys-
tems, a reduction of all other Gemins also decreases small
nuclear ribonucleoprotein assembly.14,44,46An important
observation is that small nuclear ribonucleoprotein assembly
is also decreased in cell lines derived from spinal muscular
atrophy patients45; therefore, small nuclear ribonucleopro-
tein assembly measurements in patient cells provide an addi-
tional molecular biomarker for use in clinical trials, drug
discovery experiments, and pathophysiologic investigations.
Spinal Muscular Atrophy–Relevant
How does a loss of a general function, small nuclear ribonu-
cleoprotein assembly capacity result in the selective loss of
both Sm proteins as well as small nuclear ribonucleic acids and assembles the Sm proteins onto the ribonucleic acid Sm site (discussed in the text).
Schematic of the function of the SMN complex in spliceosomal small nuclear ribonucleoprotein assembly. The SMN complex directly binds
characteristics of small nuclear ribonucleic acids that are recognized by
direct binding of the SMN complex. The minimal domain is composed
of an Sm site and an adjacent 3′ stem loop. For the SMN complex to
bind, the adjacent 3′ stem loop must be located within a short distance
of the 3′ end of the ribonucleic acid; however, the exact sequence of this
structure can vary.
The small nuclear ribonucleoprotein code. The defining
motor neurons in spinal muscular atrophy? Much work is
currently under way to address this question. In mice, small
nuclear ribonucleoprotein assembly varies markedly in dif-
ferent tissues and during development.47In the mouse
spinal cord, small nuclear ribonucleoprotein assembly activ-
ity is highest during embryonic development and then
declines after the first week of life.47This temporal pattern
coincides with the onset of myelination in the central nerv-
ous system and suggests that high levels of small nuclear
ribonucleoprotein biogenesis are required for neuronal
development. In the embryonic zebrafish, motor neuron
development is altered by reduction of SMN and can be res-
cued by injection of formed small nuclear ribonucleopro-
teins48; therefore, it is possible that reduced SMN protein
leads to reduced small nuclear ribonucleoprotein produc-
tion, which leads to changes in the ability of cells to splice
genes correctly.3,5Because each cell is faced with the exe-
cution of a unique constellation of splicing events on a
unique set of premessenger RNAs, it appears likely that the
splicing of specific premessenger RNAs that are crucial for
motor neuron survival and/or development may be altered
in spinal muscular atrophy; however, specific alterations in
messenger RNAs from spinal muscular atrophy patients or
model systems have so far not been identified.
It has already been stressed that SMN function in cells
is not likely to be limited to its role in spliceosomal ribonu-
cleoprotein assembly. SMN accumulates in the axons of
motor neurons (and in other types of neurons) during nerv-
ous system development and thus may also have functions
that are unique to neurons.47,49-51For example, it has been
suggested that SMN may function as a molecular chaper-
one for β-actin messenger RNA localization in motor
axons.52Given the large number of RNA and protein bind-
ing partners of SMN and the SMN complex, it is likely that
the number of cellular functions attributed to the SMN
complex will continue to increase; however, based on our
current understanding, it is reasonable to conclude that the
pathologic consequence of low SMN levels in spinal mus-
cular atrophy is the disruption of normal cellular RNA
metabolism required for motor neuron development and
survival. The identification of specific defects in RNA
metabolism, such as the identification of specific splicing
defects in genes that result in motor neuron loss in spinal
muscular atrophy, may provide additional therapeutic tar-
gets for this disease and will provide fundamental insights
into motor neuron biology and pathology.
This article was presented at the Neurobiology of Disease
in Children: Symposium on Spinal Muscular Atrophy, in
conjunction with the 35th annual meeting of the Child
Neurology Society, Pittsburgh, Pennsylvania, October 18-
21, 2006. This work was supported by the Association
Francaise Contre les Myopathies (A.F.M.). SJK is sup-
ported by the MDA (MDA3867). GD is an investigator
of the Howard Hughes Medical Institute.
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