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Backbone flexibility controls the activity and specificity of a protein-protein interface – specificity in snake venom metalloproteases (SVMPs)

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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.

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    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. 10.1038/nature02555.

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    Bjarnason JB, Fox JW: Hemorrhagic metalloproteinases from snake venoms. Pharmac Ther. 1994, 62: 325-372. 10.1016/0163-7258(94)90049-3.

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    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. 10.1021/ja909908y.

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Correspondence to Klaus R Liedl.

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Wallnoefer, H.G., Lingott, T., Gutiérrez, J.M. et al. Backbone flexibility controls the activity and specificity of a protein-protein interface – specificity in snake venom metalloproteases (SVMPs). J Cheminform 3, O22 (2011). https://doi.org/10.1186/1758-2946-3-S1-O22

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Keywords

  • Basement Membrane
  • Significant Alteration
  • Surface Region
  • Damage Function
  • Potential Reaction