The Caenorhabditis elegans muscle specific serpin, SRP-3, neutralizes chymotrypsin-like serine peptidases.
Members of the intracellular serpin family may help regulate apoptosis, tumor progression, and metastasis. However, their in vivo functions in the context of a whole organism have not been easily defined. To better understand the biology of these serpins, we initiated a comparative genomics study using Caenorhabditis elegans as a model organism. Previous in silico analysis suggested that the C. elegans genome harbors nine serpin-like sequences bearing significant similarities to the human clade B intracellular serpins. However, only five genes appear to encode full-length serpins with intact reactive site loops. To determine if this was the case, we have cloned and expressed a putative inhibitory-type C. elegans serpin, srp-3. Analysis of SRP-3 inhibitory activity indicated that SRP-3 was a potent inhibitor of the serine peptidases, chymotrypsin and cathepsin G. Spatial and temporal expression studies using GFP and LacZ promoter fusions indicated that SRP-3 was expressed primarily in the anterior body wall muscles, suggesting that it may play a role in muscle cell homeostasis. Combined with previous studies showing that SRP-2 is an inhibitor of the serine peptidase, granzyme B, and lysosomal cysteine peptidases, these data suggested that C. elegans expressed at least two inhibitory-type serpins with nonoverlapping expression and inhibitory profiles. Moreover, the profiles of these clade L serpins in C. elegans share significant similarities with the profiles of clade B intracellular serpin members in higher vertebrates. This degree of conservation suggests that C. elegans should prove to be a valuable resource in the study of metazoan intracellular serpin function.
UPMC Newborn Medicine Program, Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, and Magee-Womens Research Institute, Pittsburgh, Pennsylvania 15213, USA.
Stephen C
SC
Pak
Christopher
C
Tsu
Cliff J
CJ
Luke
Yuko S
YS
Askew
Gary A
GA
Silverman
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D056649:Cathepsin G; D002403:Cathepsins / Q000378:metabolism; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D003001:Cloning, Molecular; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009132:Muscles / Q000201:enzymology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000378:metabolism; D015843:Serpins / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D011993:Recombinant Fusion Proteins; C510513:SRP-3 protein, C elegans; D015843:Serpins; D002403:Cathepsins; D012697:Serine Endopeptidases; D002918:Chymotrypsin; C534094:CTSG protein, human; D056649:Cathepsin G