Protein-Protein interfaces have crucial functions in many biological processes [1]. The large interaction areas of such interfaces show complex interaction motifs. Even more challenging is the understanding of (multi-)specificity in protein-protein binding. Many proteins can bind several partners to mediate their function [2].
A perfect paradigm to study such multi-specific protein-protein interfaces are snake venom metalloproteases (SVMPs) [3]. Inherently, they bind to a variety of basement membrane proteins of capillaries, hydrolyze them, and induce profuse bleeding. However, despite having a high sequence homology, some SVMPs show a strong hemorrhagic activity, while others are (almost) inactive [4].
Our results indicate that the activity to induce hemorrhage, and thus the capability to bind the potential reaction partners, is related to the backbone flexibility in a certain surface region[4]. A subtle interplay between flexibility and rigidity of two loops seems to be the prerequisite for the proteins to carry out their damaging function. Presumably, a significant alteration in the backbone dynamics makes the difference between SVMPs that induce hemorrhage and the inactive ones.
References
- Mandell DJ, Kortemme T. Computer-aided design of functional protein interactions. Nat Chem Biol. 2009;5:797–807. doi: 10.1038/nchembio.251. [DOI] [PubMed] [Google Scholar]
- Han JD, Hao T, Goldberg DS, Berriz GF, Zhang LV, Dupuy D, Walhout AJM, Cusick ME, Roth FP, Vidal M. Evidence for dynamically organized modularity in the yeast protein-protein interaction network. Nature. 2004;430:88–93. doi: 10.1038/nature02555. [DOI] [PubMed] [Google Scholar]
- Bjarnason JB, Fox JW. Hemorrhagic metalloproteinases from snake venoms. Pharmac Ther. 1994;62:325–372. doi: 10.1016/0163-7258(94)90049-3. [DOI] [PubMed] [Google Scholar]
- Wallnoefer HG, Lingott T, Gutiérrez JM, Merfort I, Liedl KR. Backbone Flexibility Controls the Activity and Specificity of a Protein - Protein Interface: Specificity in Snake Venom Metalloproteases. J Am Chem Soc. 2010;132:10330–10337. doi: 10.1021/ja909908y. [DOI] [PubMed] [Google Scholar]