This is the page for Group Smc1 (Christine, Charlotte and Giulia)

Introduction

SMC proteins represent a large family of ATPases that participate in many aspects of higher-order chromosome organization and dynamics.SMC stands for Structural Maintenance of Chromosomes.

Eukaryotes have at least six SMC proteins in individual organisms, and they form three distinct heterodimers with specialized functions:

• A pair of SMC1 and SMC3 constitutes the core subunits of the cohesin complexes involved in sister chromatid cohesion.
• Likewise, a pair of SMC2 and SMC4 acts as the core of the condensin complexes implicated in chromosome condensation.
• A dimer composed of SMC5 and SMC6 functions as part of a yet-to-be-named octameric complex implicated in DNA repair and checkpoint responses.

Each complex contains a distinct set of non-SMC regulatory subunits.

Some organisms have variants of SMC proteins. For instance, mammals have a meiosis-specific variant of SMC1, known as SMC1B. The nematode Caenorhabditis elegans has an SMC4-variant that has a specialized role in dosage compensation.

Proper cohesion of sister chromatids is a prerequisite for the correct segregation of chromosomes during cell division. The cohesin multiprotein complex is required for sister chromatid cohesion. Most of the cohesin complexes dissociate from the chromosomes before mitosis, although those complexes at the kinetochore remain. Therefore, the encoded protein is thought to be an important part of functional kinetochores. In addition, this protein interacts with BRCA1 and is phosphorylated by ATM, indicating a potential role for this protein in DNA repair.

Gene

The SMC1A gene can be found on Chromosome X at location 53, 417, 795-53,466,343.

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Homo sapiens SMC1A

Mus musculus SMC1A

Saccharomyces cerevisiae SMC1

Protein Structure

Primary

SMC protein monomers have a modular structure and contain the following domains:

• 1) Walker A ATP-binding motif
• 2) hinge region
• 3) coiled-coil region I
• 4) coiled-coil region II
• 5) Walker B ATP-binding motif

MoreDetails

Structure of SMC1/SMC3:

Since it according to the genome browser looks like SMC1 is really conserved between species, we did a multiple sequence alignment. We compared human, mouse and yeast.

Alignment

Tertiary

SMC dimers form a V-shaped molecule with two long coiled-coil arms, each having an ATP-binding domain at its distal end. The ATP-binding domain of SMC proteins is structurally related to that of ABC transporters, a large family of transmembrane proteins that actively transport small molecules across cellular membranes. It is thought that the cycle of ATP binding and hydrolysis modulates the cycle of closing and opening of the V-shaped molecule, but the detailed mechanisms of action of SMC proteins remain to be determined.

...and what about PROTEIN-PROTEIN interaction?

(SMC1A Homo sapiens)

Disease

An X-linked form of the disorder Cornelia de Lange syndrome can be caused by mutations in the SMC1A gene (OMIM). Cornelia de Langes syndrome is a developmental disorder which affects many parts of the body, and is most often recognized on the basis of characteristic facies, such as low anterior hairline, synophrys, anteverted nares, maxillary prognathism, long philtrum, 'carp' mouth in association with prenatal and postnatal growth retardation, mental retardation and, in many cases, upper limb anomalies. This syndrome is in most cases (around 50%) caused by a mutation in the NIPBL gene, which also encodes a part of the cohesin complex. However, in 2006 Musio et al. reported 4 affected males with SMC1A mutations and many of the major features of Cornelia de Langes syndrome such as the typical facial dysmorphisms, mental retardation in the moderate to severe range, and growth deficits with feeding problems in childhood. However, the symptoms were not as severe as the ones observed in patients with NIPBL mutations, for example their hands were not malformed but the size of their hands were under the third percentile.

One patient was sporadic, the other three were related, two siblings and one cousin. The mother of the two affected siblings showed a mild clinical phenotype. In the two brothers and their cousin a 3-nt deletion at nucleotide 2493-2495 in the cDNA (accession number S78271 in genBank) was observed. This resulted in a deletion of Q832 and a D831E substitution. We haven't been able to confirm these changes, since the authors didn't mention the accession number to the original sequence. When comparing the sequence to which they linked (S78271, GenBank) with the wild type mRNA sequence (NM_006306, GenBank) using ClustalW other differences than the ones described in the article was found. This was probably due to comparing to another wt sequence than the one the authors used.

In the case where Cornelia de Langes syndrome was sporadic an A-to-C transversion at nucleotide 1478 of the cDNA sequence, which caused an E493A missense mutation, was found. This mutation was not found in the patients unaffected brother or sister. The effect of this mutation is probably damaging, according to PolyPhen (not controlled).

Deardorff et al. identified 14 additional SMCa1 mutations in patients with a mild variant of Cornelia de Lange syndrome with predominant mental retardation. Analysis of the mutant SMCa1 proteins indicated that they were likely to produce functional cohesin complexes; however, Deardorff et al. (2007) posited that they mutations may alter their chromosome binding dynamics.

Musio et al. X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations, Nature Genetics 2006 May;38(5):528-30. Epub 2006 Apr 9

Deardorff et al. ( Mutations in cohesin complex members SMC3 and SMCA1 cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation. Am. J. Hum. Genet. 80: 485-494, 2007)

X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations, Nature Genetics 2006 May;38(5):528-30. Epub 2006 Apr 9

http://ghr.nlm.nih.gov/condition=corneliadelangesyndrome + OMIM

(Interesting note: SOX2 has been excluded as a candidate for Cornelia de Lange Syndrome)

Tools and Bibliography

Useful links:

http://www.ncbi.nlm.nih.gov/

http://genome.ucsc.edu/

http://en.wikipedia.org/wiki/Main_Page

http://www.abcam.com/index.html?t=7379&pt=1&c=1040

http://www.uniprot.org