Structure of the Human MutSα DNA Lesion Recognition Complex

Abstract

Mismatch repair (MMR) ensures the fidelity of DNA replication, initiates the cellular response to certain classes of DNA damage, and has been implicated in the generation of immune diversity. Each of these functions depends on MutSalpha (MSH2*MSH6 heterodimer). Inactivation of this protein complex is responsible for tumor development in about half of known hereditary nonpolyposis colorectal cancer kindreds and also occurs in sporadic tumors in a variety of tissues. Here, we describe a series of crystal structures of human MutSalpha bound to different DNA substrates, each known to elicit one of the diverse biological responses of the MMR pathway. All lesions are recognized in a similar manner, indicating that diversity of MutSalpha-dependent responses to DNA lesions is generated in events downstream of this lesion recognition step. This study also allows rigorous mapping of cancer-causing mutations and furthermore suggests structural pathways for allosteric communication between different regions within the heterodimer.

DNA mismatch repair: Molecular mechanism, cancer, and ageing

“…Three clusters of surface mutations, which may correspond to sites of protein-protein interactions are indicated with dashed ovals. Reproduced with permission (Warren et al, 2007). …”

“…3; Warren et al, 2006Warren et al, ,2007. The structure utilized full-length MSH2 and a truncated MSH6 missing the N-terminal 340 amino acids.…”

“…HNPCC mutations have been mapped onto the three-dimensional structure of hMutSα ( Fig. 3; Warren et al, 2007). Clearly, mutations are located throughout the protein structure; the challenge is to identify informative mutations that can shed light on molecular mechanism.…”

Classification of mismatch repair gene missense variants with PON-MMR

“…The effects of MSH2 and MSH6 missense variants were studied based on the structure of the heterodimer in PDB entry 2O8B [Warren et al, 2007]. Recognition of secondary structural elements in proteins was done with STRIDE [Heinig and Frishman, 2004] and visualization with program Pymol [Schrödinger, 2010].…”

A novel complex mutation in MSH2 contributes to both Muir-Torre and Lynch Syndrome

“…This is supported by the observation that this mutation maps on to the clamp domain of MSH2 based on the recently solved crystal structures of human MutSa (MSH2-MSH6 complex). 18 Based on these structures, this clamp domain is postulated to be involved in making thus far uncharacterized, nonspecific interactions with DNA. Therefore, this mutation likely decreases the efficiency with which MSH2 recognizes and binds to certain types of DNA mismatches, or the stability of these interactions; thereby affecting the efficient functioning of the MMR system, rather than the expression of the MSH2 protein.…”