King C Y, Weiss M A
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11990-4. doi: 10.1073/pnas.90.24.11990.
SRY, a putative transcription factor encoded by the sex-determining region of the human Y chromosome, regulates a genetic switch in male development. Impairment of this switch leads to intersex abnormalities of the newborn and is observed in association with mutations in the SRY DNA-binding domain [the high-mobility-group (HMG) box]. Here we show that the SRY HMG box exhibits a novel mechanism of DNA recognition: partial intercalation of a nonpolar side chain in the DNA minor groove. Base stacking (but not base pairing) is interrupted at the site of insertion. Sequence specificity reflects topological requirements of partial intercalation rather than direct readout of base-specific functional groups. Our results predict that the SRY HMG box inserts an alpha-helix into a widened minor groove at the center of a sharp DNA bend. A similar mechanism may underlie binding of SRY and homologous HMG proteins to four-way junctions (Holliday intermediates) and other noncanonical DNA structures.
SRY是一种由人类Y染色体性别决定区域编码的假定转录因子，它调控男性发育过程中的一个基因开关。这个开关功能受损会导致新生儿出现两性畸形，并且已观察到这种情况与SRY DNA结合结构域（高迁移率族[HMG]盒）中的突变有关。我们在此表明，SRY HMG盒展现出一种新的DNA识别机制：一条非极性侧链部分插入DNA小沟。在插入位点，碱基堆积（而非碱基配对）被中断。序列特异性反映的是部分插入的拓扑学要求，而非对碱基特异性官能团的直接识别。我们的结果预测，SRY HMG盒会将一个α螺旋插入到尖锐DNA弯曲中心处变宽的小沟中。类似的机制可能是SRY和同源HMG蛋白与四向连接点（霍利迪中间体）及其他非典型DNA结构结合的基础。
