Domain (IV), the clamp domain, primarily consists of hydrophobic and charged residues. Once MutS has detected a mismatch, ATP hydrolysis stops and a severe distortions in the conformation of DNA at the mismatch site occurs. The clamp has numerous hydrophobic and charged residues, which is consistent with a role in dimerizing with the charged residues of the clamp of MSH6. In addition, it may work to stabilize the highly unfavorable state of DNA when a mismatch is recognized. The positively charged residues such as lysine and arginine can form ion pairs with the negatively charged phosphate groups on the DNA backbone. Furthermore, the negatively charged residues such as glutamate and aspartate can hydrogen bond with the sugars on the backbone
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The specify of adenine binding occurs through two hydrogen bonds with the amide backbone of a nearby isoleucine residue. The serine-rich sections suggest potential sites for Mg2+ binding. The Walker B motif is believed to be involved in stabilizing Mg2+-bound water once the metal ion coordinates to an aspartate residue.
Overall Assessment
In humans, the MMR system is composed of seven proteins that work in a highly synchronized fashion to perform DNA mismatch repair: MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2. These seven proteins form several complexes, including: MutSα, a MSH2•MSH6 heterodimer; MutSβ, a MSH2•MSH3 heterodimer; MutLα, a MLH1•PMS2 heterodimer—and together with the PCNA replication clamp, DNA polymerase δ, and the single-stranded DNA binding protein RPA, the various complexes work synchronously to repair DNA mismatches.20 The structure and function of the first step—recognition of a mismatch but MutS—was discussed (Figure …show more content…
sapiens, M. musculus, and S. cerevisiae provide an overview of the residues and motifs present in MMR, it is sufficient only for inferring the many factors that contribute to disease via MMR mutations. MSH2 is believed to be a facilitator in mismatch repair, stabilizing MSH6 as it recruits other actors in the MMR pathway. Despite the seemingly peripheral role of MSH2, it is known that any major changes to its structure limit its binding to MSH6—and without MSH2, MSH6 does not survive for very long post translation. The downregulation of MSH2 has been implicated in numerous types of cancer, including breast9 and colon2, 18, 22 cancers, endometrial carcinoma, and malignancies of the stomach, small bowel, ovaries, upper uroepithelial tract, biliary tract, skin and brain.X The primary structure of one component of the MutSα dimer, MSH2, has provided insight into the protein and the conclusion that MSH2—and the MMR system in general—is unquestionably
The specify of adenine binding occurs through two hydrogen bonds with the amide backbone of a nearby isoleucine residue. The serine-rich sections suggest potential sites for Mg2+ binding. The Walker B motif is believed to be involved in stabilizing Mg2+-bound water once the metal ion coordinates to an aspartate residue.
Overall Assessment
In humans, the MMR system is composed of seven proteins that work in a highly synchronized fashion to perform DNA mismatch repair: MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2. These seven proteins form several complexes, including: MutSα, a MSH2•MSH6 heterodimer; MutSβ, a MSH2•MSH3 heterodimer; MutLα, a MLH1•PMS2 heterodimer—and together with the PCNA replication clamp, DNA polymerase δ, and the single-stranded DNA binding protein RPA, the various complexes work synchronously to repair DNA mismatches.20 The structure and function of the first step—recognition of a mismatch but MutS—was discussed (Figure …show more content…
sapiens, M. musculus, and S. cerevisiae provide an overview of the residues and motifs present in MMR, it is sufficient only for inferring the many factors that contribute to disease via MMR mutations. MSH2 is believed to be a facilitator in mismatch repair, stabilizing MSH6 as it recruits other actors in the MMR pathway. Despite the seemingly peripheral role of MSH2, it is known that any major changes to its structure limit its binding to MSH6—and without MSH2, MSH6 does not survive for very long post translation. The downregulation of MSH2 has been implicated in numerous types of cancer, including breast9 and colon2, 18, 22 cancers, endometrial carcinoma, and malignancies of the stomach, small bowel, ovaries, upper uroepithelial tract, biliary tract, skin and brain.X The primary structure of one component of the MutSα dimer, MSH2, has provided insight into the protein and the conclusion that MSH2—and the MMR system in general—is unquestionably