SMC4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSMC4, CAP-C, CAPC, SMC-4, SMC4L1, hCAP-C, structural maintenance of chromosomes 4
External IDsOMIM: 605575 MGI: 1917349 HomoloGene: 4015 GeneCards: SMC4
Orthologs
SpeciesHumanMouse
Entrez

10051

70099

Ensembl

ENSG00000113810

ENSMUSG00000034349

UniProt

Q9NTJ3

Q8CG47

RefSeq (mRNA)

NM_001002799
NM_001002800
NM_001288753
NM_005496

NM_133786
NM_001356976

RefSeq (protein)

NP_001002800
NP_001275682
NP_005487

NP_598547
NP_001343905

Location (UCSC)Chr 3: 160.4 – 160.43 MbChr 3: 68.91 – 68.94 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structural maintenance of chromosomes protein 4 (SMC-4) also known as chromosome-associated polypeptide C (CAP-C) or XCAP-C homolog is a protein that in humans is encoded by the SMC4 gene.[5][6][7] SMC-4 is a core subunit of condensin I and II, large protein complexes involved in high order chromosome organization,[8] including condensation and segregation.[9] SMC-4 protein is commonly associated with the SMC-2 protein, another protein complex within the SMC protein family. SMC-4 dimerizes with SMC-2, creating the flexible and dynamic structure of the condensin holocomplex.[8] An over-expression of the SMC-4 protein is shown to impact carcinogenesis.[10][11][9]

Structure and interactions

Structure of a condensin protein holocomplex, displaying the SMC-4/SMC-2 heterodimer, and additional subunits. Kleisin is also depicted (blue).

The primary 5 domain structure of SMC proteins is highly conserved among species. The basic structure of SMC proteins are characterized by a non-helical hinge group, separated by two anti-parallel α-helical coiled-coil domains, along with two Amino-terminal globular domains containing ATP hydrolytic sites, or nucleotide-binding motifs located at the C-terminus and N-terminus called the Walker A and Walker B motifs.[12]

In eukaryotes, dimerization is mediated by the self-folding of the non-helical hinge group on the SMC protein. Dimerization occurs at the non-helical hinge group of SMC-4, which then associates with the non-helical hinge group of SMC-2, creating a V-shaped heterodimeric structure. the holocomplex of condensin contains the SMC-4 and SMC-2 heterodimer subunits, along with 3 other non-SMC subunits, CAP-D2, CAP-G, and CAP-H.[9]

In the condensin holocomplex, a protein subunit called kleisin joins the C-terminus and N-terminus ATPase end domains of both SMC-4 and SMC-2 proteins. when the condensin holocomplex is bound with ATP at these end domains, the condensin will assume a "closed" conformation state.[8] SMC-4 is a dynamic and flexible protein, allowing different domain components to occasionally interact with others. This is speculated to be involved in the mechanical ability of the complex when associated with chromosomes.[8] In budding yeast, these interactions may result in open "O" appearances, or collapsed B-shaped states as a result of its dynamic ability.[13]

Clinical significance

The SMC-4 protein is associated with abnormal cell and tumor growth, and involved with migration and invasion. In general, the presence of over-expressed SMC-4 proteins is thought to be correlated with carcinogenesis.[10]

It is found that an over-expression or down-regulation of the SMC-4 protein alters TGFβ/Smad signaling pathways in glioma cells. SMC-4-transduced glioma cells showed activation of the TGFβ/Smad signaling pathway which was not present in SMC-4 silenced glioma cells. This pathway was shown to be correlated with an "aggressive" behavioral phenotype in glioma cells. An over-expression of SMC-4 can induce a higher rate of proliferation, and ultimately increased invasive capability. A down-regulation of SMC-4 reduced this quality.[10]

The SMC-4 protein is involved with normal lung development however, adenocarcinoma lung tissue shows an over-expression of SMC-4. additionally, SMC-4 may act as independent prognostic factor for carcinogenesis and lung adenocarcinoma.[9]

Studies suggest that over-expression of the SMC-4 protein in human liver tissue may be correlated with progression of hepatocellular carcinoma.[11]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000113810 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000034349 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: SMC4 structural maintenance of chromosomes 4".
  6. ↑ Nishiwaki T, Daigo Y, Kawasoe T, Nagasawa Y, Ishiguro H, Fujita M, et al. (Jun 1999). "Isolation and characterization of a human cDNA homologous to the Xenopus laevis XCAP-C gene belonging to the structural maintenance of chromosomes (SMC) family". Journal of Human Genetics. 44 (3): 197–202. doi:10.1007/s100380050142. PMID 10319587.
  7. ↑ Schmiesing JA, Ball AR, Gregson HC, Alderton JM, Zhou S, Yokomori K (October 1998). "Identification of two distinct human SMC protein complexes involved in mitotic chromosome dynamics". Proceedings of the National Academy of Sciences of the United States of America. 95 (22): 12906–12911. Bibcode:1998PNAS...9512906S. doi:10.1073/pnas.95.22.12906. PMC 23650. PMID 9789013.
  8. 1 2 3 4 Eeftens JM, Katan AJ, Kschonsak M, Hassler M, de Wilde L, Dief EM, et al. (March 2016). "Condensin Smc2-Smc4 Dimers Are Flexible and Dynamic". Cell Reports. 14 (8): 1813–1818. doi:10.1016/j.celrep.2016.01.063. PMC 4785793. PMID 26904946.
  9. 1 2 3 4 Zhang C, Kuang M, Li M, Feng L, Zhang K, Cheng S (September 2016). "SMC4, which is essentially involved in lung development, is associated with lung adenocarcinoma progression". Scientific Reports. 6 (1): 34508. Bibcode:2016NatSR...634508Z. doi:10.1038/srep34508. PMC 5043270. PMID 27687868.
  10. 1 2 3 Jiang L, Zhou J, Zhong D, Zhou Y, Zhang W, Wu W, et al. (March 2017). "Overexpression of SMC4 activates TGFβ/Smad signaling and promotes aggressive phenotype in glioma cells". Oncogenesis. 6 (3): e301. doi:10.1038/oncsis.2017.8. PMC 5533949. PMID 28287612.
  11. 1 2 Zhou B, Chen H, Wei D, Kuang Y, Zhao X, Li G, et al. (June 2014). "A novel miR-219-SMC4-JAK2/Stat3 regulatory pathway in human hepatocellular carcinoma". Journal of Experimental & Clinical Cancer Research. 33 (1): 55. doi:10.1186/1756-9966-33-55. PMC 4096530. PMID 24980149.
  12. ↑ Hirano T (February 2002). "The ABCs of SMC proteins: two-armed ATPases for chromosome condensation, cohesion, and repair". Genes & Development. 16 (4): 399–414. doi:10.1101/gad.955102. PMID 11850403. S2CID 45664625.
  13. ↑ Ryu JK, Katan AJ, van der Sluis EO, Wisse T, de Groot R, Haering CH, Dekker C (December 2020). "The condensin holocomplex cycles dynamically between open and collapsed states". Nature Structural & Molecular Biology. 27 (12): 1134–1141. doi:10.1038/s41594-020-0508-3. PMID 32989304. S2CID 222146992.

Further reading

  • SMC4 human gene location in the UCSC Genome Browser.
  • SMC4 human gene details in the UCSC Genome Browser.
  • PDBe-KB provides an overview of all the structure information available in the PDB for Human Structural maintenance of chromosomes protein 4 (SMC4)
  • PDBe-KB provides an overview of all the structure information available in the PDB for Mouse Structural maintenance of chromosomes protein 4 (SMC4)
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