Activation of cathepsin L by the cathelin-like domain of protegrin-3.
The cathelin-like domain (CLD) of the antimicrobial cathelicidin family constitutes a unique protein family with structural similarity to cystatins, the cysteine protease inhibitors. CLDs are derived from the processed amino-terminal prosequence of the cathelicidin precursors with conservation across the vertebrate lineage ranging from fish to human. Initial attempt to characterize a possible inhibitory activity of protegrin-3 (PG3) CLD protein (a member of the multigene family of porcine cathelicidins) against several proteases led to an unexpected finding that PG3 CLD efficiently activated rather than inhibited human cathepsin L. Partial deletion of the L2 loop of PG3 CLD, a structurally equivalent region important in interaction of cystatins with proteases, significantly decreased its activating effect on cathepsin L. A complex model based on this functional loop was proposed to explain this unexpected effect, in which evolutionary emergence of completely opposite biological activity could be associated with structural discrepancies of the loop due to sequence variations between pig and human. Our results provide new insights into deeper understanding of the immune-related biological activity of this so-called pro-domain of the cathelicidin family.
Zhu
Shunyi
S
Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China. Zhusy@ioz.ac.cn
Wei
Liang
L
Yamasaki
Kenshi
K
Gallo
Richard L
RL
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D054804:Cathelicidins; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism*; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013552:Swine / Q000276:immunology
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D011994:Recombinant Proteins; C094881:protegrin-3; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L