Structural Insights into the Protease-like Antigen Plasmodium falciparum SERA5 and Its Noncanonical Active-Site Serine

Hodder, AN; Malby, RL; Clarke, OB; Fairlie, WD; Colman, PM; Crabb, BS; Smith, BJ

Author(s): Hodder, AN; Malby, RL; Clarke, OB; Fairlie, WD; Colman, PM; Crabb, BS; Smith, BJ;
Details: Publication Year 2009-09-11,Volume 392,Issue #1,Page 154-165
Journal Title: JOURNAL OF MOLECULAR BIOLOGY
Publication Type: Journal Article
Abstract: The sera genes of the malaria-causing parasite Plasmodium encode a family of unique proteins that are maximally expressed at the time of egress of parasites from infected red blood cells. These multi-domain proteins are unique, containing a central papain-like cysteine-protease fragment enclosed between the disulfide-linked N- and C-terminal domains. However, the central fragment of several members of this family, including serine repeat antigen 5 (SERA5), contains a serine (S596) in place of the active-site cysteine. Here we report the crystal structure of the central protease-like domain of Plasmodium falciparum SERA5, revealing a number of anomalies in addition to the putative nucleophilic serine: (1) the structure of the putative active site is not conducive to binding substrate in the canonical cysteine-protease manner; (2) the side chain of D594 restricts access of substrate to the putative active site; and (3) the S(2) specificity pocket is occupied by the side chain of Y735, reducing this site to a small depression on the protein surface. Attempts to determine the structure in complex with known inhibitors were not successful. Thus, despite having revealed its structure, the function of the catalytic domain of SERA5 remains an enigma. (C) 2009 Elsevier Ltd. All rights reserved.
Publisher: ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
Keywords: RAY CRYSTAL-STRUCTURE; BLOOD STAGE ANTIGEN; AMINO-ACID-SEQUENCE; CYSTEINE PROTEASE; CATHEPSIN-L; SUBSTRATE-SPECIFICITY; MALARIA PARASITE; CONFORMATIONAL FLEXIBILITY; ANGSTROM RESOLUTION; MULTIGENE FAMILY
Publisher's Version: https://doi.org/10.1016/j.jmb.2009.07.007
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2009-09-11 12:00:00