Backbone Flexibility Controls the Activity and Specificity of a Protein−Protein Interface: Specificity in Snake Venom Metalloproteases

• Published in: Journal of the American Chemical Society 2010-08, Vol.132 (30), p.10330-10337
• Main Authors: Wallnoefer, Hannes G, Lingott, Torsten, Gutiérrez, José María, Merfort, Irmgard, Liedl, Klaus R
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Crystallography, X-Ray; Metalloproteases - chemistry; Metalloproteases - metabolism; Molecular Dynamics Simulation; Molecular Sequence Data; Protein Binding; Protein Conformation; Sequence Alignment; Snake Venoms - chemistry; Snake Venoms - metabolism; Snakes - metabolism
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja909908y

Protein−protein interfaces have crucial functions in many biological processes. 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. A perfect paradigm to study such multispecific protein−protein interfaces are snake venom metalloproteases (SVMPs). 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. We present computer simulations indicating 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. 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.