4.4 Article

Crystallography and protein-protein interactions: biological interfaces and crystal contacts

Journal

BIOCHEMICAL SOCIETY TRANSACTIONS
Volume 36, Issue -, Pages 1438-1441

Publisher

PORTLAND PRESS LTD
DOI: 10.1042/BST0361438

Keywords

acyl-CoA thioesterase 7 (Acot7); platelet glycoprotein Ib alpha; protein-protein interaction; structural biology; thrombin; X-ray crystallography

Funding

  1. Australian Research Council Federation Fellow
  2. NHMRC (National Health and Medical Research Council) Honorary Research Fellow

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Crystallography is commonly used for studying the structures of protein-protein complexes. However, a crystal structure does not define a unique protein-protein interface, and distinguishing a 'biological interface' from 'crystal contacts' is often not straightforward. A number of computational approaches exist for distinguishing them, but their error rate is high, emphasizing the need to obtain further data on the biological interface using complementary structural and functional approaches. in addition to reviewing the computational and experimental approaches for addressing this problem, we highlight two relevant examples. The first example from our laboratory involves the structure of acyl-CoA thioesterase 7, where each domain of this two-domain protein was crystallized separately, but both yielded a non-functional assembly. The structure of the full-length protein was uncovered using a combination of complementary approaches including chemical cross-linking, analytical ultracentrifugation and mutagenesis. The second example involves the platelet glycoprotein Ib alpha-thrombin complex. Two groups reported the crystal structures of this complex, but all the interacting interfaces differed between the two structures. Our computational analysis did not fully resolve the reasons for the discrepancies, but provided interesting insights into the system. This review highlights the need to complement crystallographic studies with complementary experimental and computational approaches.

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