IκBα和IκBβ对NF-κB核定位信号的诱导契合、折叠及识别

Induced fit, folding, and recognition of the NF-kappaB-nuclear localization signals by IkappaBalpha and IkappaBbeta.

作者信息

Lätzer Joachim, Papoian Garegin A, Prentiss Michael C, Komives Elizabeth A, Wolynes Peter G

机构信息

Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0371, USA.

出版信息

J Mol Biol. 2007 Mar 16;367(1):262-74. doi: 10.1016/j.jmb.2006.12.006. Epub 2006 Dec 15.

DOI:10.1016/j.jmb.2006.12.006

PMID:17257619

Abstract

Protein structure prediction codes based on the associative memory Hamiltonian were used to probe the binding modes between the nuclear localization signal (NLS) polypeptide of NF-kappaB and the inhibitors IkappaBalpha and IkappaBbeta. Experimentally, it is known that the NLS polypeptide is unstructured in the NF-kappaB complex with DNA but it forms an extended helical structure with the NLS (residues 301-304) between the two helices in the NF-kappaB/IkappaBalpha complex. The simulations included the NF-kappaB(p65) and (p50) NLS polypeptides and various mutants alone and in the presence of IkappaBalpha and IkappaBbeta. The simulations predict that the NLS polypeptide by itself binds tightly to IkappaBalpha and IkappaBbeta. In the NF-kappaB (p50/p65) heterodimer, the p50 NLS is predicted to remain free to bind to importin alpha. In the interaction with IkappaBalpha, both p65 NLSs are predicted to be bound. In IkappaBbeta, the NLS polypeptide binds to two binding sites, as seen in the crystal structure, with one site heavily favored for stable binding.

摘要

基于关联记忆哈密顿量的蛋白质结构预测代码被用于探究核因子κB（NF-κB）的核定位信号（NLS）多肽与抑制剂IκBα和IκBβ之间的结合模式。在实验中，已知NLS多肽在与DNA形成的NF-κB复合物中是无结构的，但在NF-κB/IκBα复合物中，它与两个螺旋之间的NLS（残基301 - 304）形成了一个延伸的螺旋结构。模拟包括单独的NF-κB（p65）和（p50）NLS多肽以及各种突变体，以及在存在IκBα和IκBβ的情况下。模拟预测NLS多肽自身能紧密结合IκBα和IκBβ。在NF-κB（p50/p65）异源二聚体中，预测p50 NLS可自由结合输入蛋白α。在与IκBα的相互作用中，预测两个p65 NLS均会被结合。在IκBβ中，如晶体结构所示，NLS多肽与两个结合位点结合，其中一个位点强烈倾向于稳定结合。