In Vitro Regulatory Effect of Epididymal Serpin CRES on Protease Activity of Proprotein Convertase PC4/PCSK4

Author(s): P. Mishra, Q. Qiu, A. Gruslin, Y. Hidaka, M. Mbikay, A. Basak

Journal Name: Current Molecular Medicine

Volume 12 , Issue 8 , 2012

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Abstract:

PC4 or PCSK4 belongs to the 9-member superfamily of mammalian subtilases collectively called Proprotein Convertases or Proprotein Convertase Subtilisin/Kexins that convert inactive precursor proteins into their active mature forms by endoproteolytic cleavage. PC4-activity plays a crucial role in mammalian fertilization via activation of sperm surface proteins. PC4 knockout mice exhibit severely impaired male fertility due to premature sperm acrosome reaction. Regulation of sperm-PC4 activity during its storage and transport through epididymis is an important determinant for ultimate egg-binding and fertilizing capacities of sperms. Herein we show that epididymal serpin CRES (cystatin related epididymal spermatogenic) recombinant protein inhibits PC4 activity in vitro in a differential manner when measured against the fluorogenic substrate Boc- RVRR-MCA depending on its oligomeric state. Thus while CRES-dimer exhibits Ki ~8 μM, the corresponding monomer showed Ki > 100 μM. Both forms also blocked PC4-mediated processing of human proIGF-2 in human placenta tropoblast cell line with dimer being more efficient. Using specific inhibitors and substrates, we also demonstrated the presence of PC4-like activity and CRES protein in varying levels in the fluids of various epididymal compartments. Our observations suggest a potential function of CRES as a regulator of PC4 in sperm-egg interaction and fertilization.

Keywords: Proprotein convertase 4, proprotein convertase subtilisin kexin 4, serpin, epididymal fluid, cystatin related epididymal spermatogenic, inhibitor, protein aggregation, proprotein processing, yeast kexin, bacterial subtilisin, proneuropeptides, prohormones, maturation, autocatalysis, fertilization.

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Article Details

VOLUME: 12
ISSUE: 8
Year: 2012
Page: [1050 - 1067]
Pages: 18
DOI: 10.2174/156652412802480961
Price: $65

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