PMC:4528928 / 991-3602 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4528928","sourcedb":"PMC","sourceid":"4528928","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4528928","text":"1. Introduction   \nPathogenic mutations in the DNA mismatch-repair gene MLH1 (MutL homolog 1) are associated with a predisposition to Lynch syndrome (Bronner et al., 1994 ▸; Papadopoulos et al., 1994 ▸), a hereditary cancer syndrome that accounts for 2–4% of all colorectal cancer cases in the US (Aaltonen et al., 1998 ▸; Hampel et al., 2005 ▸, 2008 ▸; Lynch \u0026 de la Chapelle, 2003 ▸). Mismatch repair (MMR) is a complex, multicomponent process that is coordinated by a number of distinct DNA-repair factors. MLH1 homologs are conserved across all domains of life and are essential components of MMR (Lin et al., 2007 ▸). Human MLH1 (hMLH1) is a 756-amino-acid, 84 kDa protein that can be roughly divided into two halves: an N-terminal domain (NTD), where the ATPase activity resides, and a C-terminal domain (CTD), which is the site of dimerization with MLH1 paralogs (Guerrette et al., 1999 ▸). In higher eukaryotes, the MLH1 and PMS2 (postmeotic segregation increased 2) paralogs form a heterodimeric complex, MutLα. Once a lesion has been identified and isolated by the MutS mismatch-recognition complex, MutLα is recruited (Fukui, 2010 ▸; Martín-López \u0026 Fishel, 2013 ▸) and, via its C-terminal endonuclease activity (Kadyrov et al., 2006 ▸), generates nicks in the heteroduplex 3′ and 5′ to the mismatch that facilitate excision and replicative repair (Kadyrov et al., 2006 ▸, 2007 ▸; Modrich, 2006 ▸). While other roles for MutLα have been proposed, these are less well understood (Her et al., 2002 ▸; Liu et al., 2010 ▸; McVety et al., 2005 ▸; Pedrazzi et al., 2001 ▸; Yanamadala \u0026 Ljungman, 2003 ▸). Whilst the exact details remain unclear, the ability of MLH1 to interact with adenine nucleotides is an important factor in MMR, inducing large conformational changes in the protein (Sacho et al., 2008 ▸). Mutations that impair ATP binding or hydrolysis have a severe effect on in vitro MMR activity (Tomer et al., 2002 ▸; Johnson et al., 2010 ▸). In addition, ATP binding is required for the interaction of MutLα with MutSα, with MLH1 predominantly being responsible for this interaction (Plotz et al., 2003 ▸).\nIn this report, we present the X-ray crystal structure of a ternary Mg–ADP complex of the human MLH1 NTD domain determined to 2.30 Å resolution, which is the first report of a human MLH1 structure. As missense variants that disrupt the structure and/or function of this domain have the potential to cause disease, our structure helps to provide a direct mechanistic explanation to support the functional effect of MLH1 variants identified in patients who receive clinical genetic testing.","divisions":[{"label":"Title","span":{"begin":4,"end":19}}],"tracks":[]}