Structure of the human MutSalpha DNA lesion recognition complex.
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.
Warren
Joshua J
JJ
Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
Pohlhaus
Timothy J
TJ
Changela
Anita
A
Iyer
Ravi R
RR
Modrich
Paul L
PL
Beese
Lorena S
LS
D000244:Adenosine Diphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D020137:Base Pair Mismatch; D001665:Binding Sites; D003110:Colonic Neoplasms / Q000235:genetics; D017124:Conserved Sequence; D004261:DNA Replication; D006801:Humans; D008274:Magnesium / Q000378:metabolism; D008958:Models, Molecular; D051719:MutS DNA Mismatch-Binding Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D016415:Sequence Alignment
D000244:Adenosine Diphosphate; D051719:MutS DNA Mismatch-Binding Protein; D008274:Magnesium