SMC4 explained

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.^{[1] [2] [3]} SMC-4 is a core subunit of condensin I and II, large protein complexes involved in high order chromosome organization,^[4] including condensation and segregation.^[5] 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.^[4] An over-expression of the SMC-4 protein is shown to impact carcinogenesis.^{[6] [7] [5]}

Structure and interactions

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.^[8]

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.^[5]

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.^[4] 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. In budding yeast, these interactions may result in open "O" appearances, or collapsed B-shaped states as a result of its dynamic ability.^[9]

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.^[6]

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.

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.^[5]

Studies suggest that over-expression of the SMC-4 protein in human liver tissue may be correlated with progression of hepatocellular carcinoma.^[7]

Further reading

• Hirano T . The ABCs of SMC proteins: two-armed ATPases for chromosome condensation, cohesion, and repair . Genes & Development . 16 . 4 . 399–414 . February 2002 . 11850403 . 10.1101/gad.955102 . free .
• Ball AR, Yokomori K . The structural maintenance of chromosomes (SMC) family of proteins in mammals . Chromosome Research . 9 . 2 . 85–96 . 2001 . 11321372 . 10.1023/A:1009287518015 . 23761326 .
• Ham MF, Takakuwa T, Rahadiani N, Tresnasari K, Nakajima H, Aozasa K . Condensin mutations and abnormal chromosomal structures in pyothorax-associated lymphoma . Cancer Science . 98 . 7 . 1041–1047 . July 2007 . 17488335 . 10.1111/j.1349-7006.2007.00500.x . 25888221 . 11158810 .
• Nousiainen M, Silljé HH, Sauer G, Nigg EA, Körner R . Phosphoproteome analysis of the human mitotic spindle . Proceedings of the National Academy of Sciences of the United States of America . 103 . 14 . 5391–5396 . April 2006 . 16565220 . 1459365 . 10.1073/pnas.0507066103 . free . 2006PNAS..103.5391N .
• Geiman TM, Sankpal UT, Robertson AK, Chen Y, Mazumdar M, Heale JT, Schmiesing JA, Kim W, Yokomori K, Zhao Y, Robertson KD . 6 . Isolation and characterization of a novel DNA methyltransferase complex linking DNMT3B with components of the mitotic chromosome condensation machinery . Nucleic Acids Research . 32 . 9 . 2716–2729 . 2004 . 15148359 . 419596 . 10.1093/nar/gkh589 .
• Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A . 6 . Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs . Genome Research . 11 . 3 . 422–435 . March 2001 . 11230166 . 311072 . 10.1101/gr.GR1547R .
• Kimura K, Cuvier O, Hirano T . Chromosome condensation by a human condensin complex in Xenopus egg extracts . The Journal of Biological Chemistry . 276 . 8 . 5417–5420 . February 2001 . 11136719 . 10.1074/jbc.C000873200 . free .
• Schmiesing JA, Gregson HC, Zhou S, Yokomori K . A human condensin complex containing hCAP-C-hCAP-E and CNAP1, a homolog of Xenopus XCAP-D2, colocalizes with phosphorylated histone H3 during the early stage of mitotic chromosome condensation . Molecular and Cellular Biology . 20 . 18 . 6996–7006 . September 2000 . 10958694 . 88774 . 10.1128/MCB.20.18.6996-7006.2000 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–156 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–174 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .

External links

• • • 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)

Notes and References

1. Web site: Entrez Gene: SMC4 structural maintenance of chromosomes 4 .
2. Nishiwaki T, Daigo Y, Kawasoe T, Nagasawa Y, Ishiguro H, Fujita M, Furukawa Y, Nakamura Y . 6 . 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 . Jun 1999 . 10319587 . 10.1007/s100380050142 . free .
3. Schmiesing JA, Ball AR, Gregson HC, Alderton JM, Zhou S, Yokomori K . 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 . October 1998 . 9789013 . 23650 . 10.1073/pnas.95.22.12906 . 1998PNAS...9512906S . free .
4. Eeftens JM, Katan AJ, Kschonsak M, Hassler M, de Wilde L, Dief EM, Haering CH, Dekker C . 6 . Condensin Smc2-Smc4 Dimers Are Flexible and Dynamic . English . Cell Reports . 14 . 8 . 1813–1818 . March 2016 . 26904946 . 4785793 . 10.1016/j.celrep.2016.01.063 .
5. Zhang C, Kuang M, Li M, Feng L, Zhang K, Cheng S . SMC4, which is essentially involved in lung development, is associated with lung adenocarcinoma progression . Scientific Reports . 6 . 1 . 34508 . September 2016 . 27687868 . 5043270 . 10.1038/srep34508 . 2016NatSR...634508Z .
6. Jiang L, Zhou J, Zhong D, Zhou Y, Zhang W, Wu W, Zhao Z, Wang W, Xu W, He L, Ma Y, Hu Y, Zhang W, Li J . 6 . Overexpression of SMC4 activates TGFβ/Smad signaling and promotes aggressive phenotype in glioma cells . Oncogenesis . 6 . 3 . e301 . March 2017 . 28287612 . 5533949 . 10.1038/oncsis.2017.8 .
7. Zhou B, Chen H, Wei D, Kuang Y, Zhao X, Li G, Xie J, Chen P . 6 . A novel miR-219-SMC4-JAK2/Stat3 regulatory pathway in human hepatocellular carcinoma . Journal of Experimental & Clinical Cancer Research . 33 . 1 . 55 . June 2014 . 24980149 . 4096530 . 10.1186/1756-9966-33-55 . free .
8. Hirano T . The ABCs of SMC proteins: two-armed ATPases for chromosome condensation, cohesion, and repair . Genes & Development . 16 . 4 . 399–414 . February 2002 . 11850403 . 10.1101/gad.955102 . 45664625 . free .
9. Ryu JK, Katan AJ, van der Sluis EO, Wisse T, de Groot R, Haering CH, Dekker C . The condensin holocomplex cycles dynamically between open and collapsed states . Nature Structural & Molecular Biology . 27 . 12 . 1134–1141 . December 2020 . 32989304 . 10.1038/s41594-020-0508-3 . 222146992 .