5v3g

Publication Abstract from PubMed

PRDM9 is the only mammalian gene that has been associated with speciation. The PR/SET domain 9 (PRDM9) protein is a major determinant of meiotic recombination hotspots, and acts through sequence-specific DNA binding via its C2H2 zinc finger (ZF) tandem array, which is highly polymorphic within and between species. The most common human variant, PRDM9 allele A (PRDM9a), contains 13 fingers (ZF1-13). Allele C (PRDM9c) is the second-most common among African populations, and differs from PRDM9a by an arginine-to-serine change (R764S) in ZF9, and by replacement of ZF11 with two other fingers, yielding 14 fingers in PRDM9c. Here we co-crystallized the six-finger fragment ZF8-13 of PRDM9c, in complex with an oligonucleotide representing a known PRDM9c-specific hotspot sequence, and compared the structure to that of a characterized PRDM9a specific complex. There are three major differences. First, Ser-764 in ZF9 allows PRDM9c to accommodate a variable base, while PRDM9a Arg-764 recognizes a conserved guanine. Second, the two-finger expansion of ZF11 allows PRDM9c to recognize three-base-pair longer sequences. A tryptophan in the additional ZF interacts with a conserved thymine methyl group. Third, an Arg-Asp dipeptide immediately preceding the ZF helix, conserved in two PRDM9a fingers and three PRDM9c fingers, permits adaptability to variations from a C:G base pair (G-Arg interaction) to a G:C base pair (C-Asp interaction). This Arg-Asp conformational switch allows identical ZF modules to recognize different sequences. Our findings illuminate the molecular mechanisms for flexible and conserved binding of human PRDM9 alleles to their cognate DNA sequences.

Structural basis of human PRDM9 allele C specific recognition of its cognate DNA sequence.,Patel A, Zhang X, Blumenthal RM, Cheng X J Biol Chem. 2017 Aug 11. pii: jbc.M117.805754. doi: 10.1074/jbc.M117.805754. PMID:28801461^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.