Urologic Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2937-42. doi: 10.1073/pnas.1114414109. Epub 2012 Feb 6.
Hsp90 is an essential and highly conserved modular molecular chaperone whose N and middle domains are separated by a disordered region termed the charged linker. Although its importance has been previously disregarded, because a minimal linker length is sufficient for Hsp90 activity, the evolutionary persistence of extensive charged linkers of divergent sequence in Hsp90 proteins of most eukaryotes remains unexplained. To examine this question further, we introduced human and plasmodium native and length-matched artificial linkers into yeast Hsp90. After evaluating ATPase activity and biophysical characteristics in vitro, and chaperone function in vivo, we conclude that linker sequence affects Hsp90 function, cochaperone interaction, and conformation. We propose that the charged linker, in addition to providing the flexibility necessary for Hsp90 domain rearrangements--likely its original purpose--has evolved in eukaryotes to serve as a rheostat for the Hsp90 chaperone machine.
热休克蛋白 90（Hsp90）是一种必需且高度保守的模块化分子伴侣，其 N 端和中间结构域由一个称为带电连接体的无规区隔开。尽管之前人们忽视了它的重要性，因为最小的连接体长度足以维持 Hsp90 的活性，但在大多数真核生物的 Hsp90 蛋白中，广泛存在的、序列不同的带电连接体的进化持久性仍然没有得到解释。为了进一步研究这个问题，我们将人类和疟原虫的天然和长度匹配的人工连接体引入酵母 Hsp90 中。在评估了体外的 ATP 酶活性和生物物理特性，以及体内的伴侣功能后，我们得出结论，连接体序列影响 Hsp90 的功能、共伴侣相互作用和构象。我们提出，带电连接体除了提供 Hsp90 结构域重排所需的灵活性（可能是其最初的目的）之外，在真核生物中还进化为 HSP90 伴侣机器的变阻器。
