5u5r

<StructureSection load='5u5r' size='340' side='right' caption='[[5u5r]], [[Resolution|resolution]] 2.10&Aring;' scene=''>

<table><tr><td colspan='2'>[[5u5r]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U5R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5U5R FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene></td></tr>

<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5u5p|5u5p]]</td></tr>

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5u5r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u5r OCA], [http://pdbe.org/5u5r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u5r RCSB], [http://www.ebi.ac.uk/pdbsum/5u5r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u5r ProSAT]</span></td></tr>

== Disease ==

[[http://www.uniprot.org/uniprot/PMS2_HUMAN PMS2_HUMAN]] Defects in PMS2 are the cause of hereditary non-polyposis colorectal cancer type 4 (HNPCC4) [MIM:[http://omim.org/entry/614337 614337]]. Mutations in more than one gene locus can be involved alone or in combination in the production of the HNPCC phenotype (also called Lynch syndrome). Most families with clinically recognized HNPCC have mutations in either MLH1 or MSH2 genes. HNPCC is an autosomal, dominantly inherited disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early onset colorectal carcinoma (CRC) and extra-colonic cancers of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world, and accounts for 15% of all colon cancers. Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Clinically, HNPCC is often divided into two subgroups. Type I: hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II: patients have an increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term 'suspected HNPCC' or 'incomplete HNPCC' can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected.<ref>PMID:15887124</ref> <ref>PMID:18178629</ref> Defects in PMS2 are a cause of mismatch repair cancer syndrome (MMRCS) [MIM:[http://omim.org/entry/276300 276300]]; also known as Turcot syndrome or brain tumor-polyposis syndrome 1 (BTPS1). MMRCS is an autosomal dominant disorder characterized by malignant tumors of the brain associated with multiple colorectal adenomas. Skin features include sebaceous cysts, hyperpigmented and cafe au lait spots.<ref>PMID:7661930</ref> <ref>PMID:9419979</ref> <ref>PMID:15077197</ref> <ref>PMID:17557300</ref>

[[http://www.uniprot.org/uniprot/IMA1_MOUSE IMA1_MOUSE]] Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. [[http://www.uniprot.org/uniprot/PMS2_HUMAN PMS2_HUMAN]] Component of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MLH1 to form MutL alpha. DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH6) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MulL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages.<ref>PMID:16873062</ref> <ref>PMID:18206974</ref>

[[Category: Barros, A C]]

[[Category: Dreyer, T R]]

[[Category: Fontes, M R]]

[[Category: Kobe, B]]

[[Category: Takeda, A A]]

[[Category: Velazquez-Campoy, A]]

[[Category: Importin-alpha]]

[[Category: Nl]]

[[Category: Nuclear transport]]

[[Category: Transport protein]]