The reactive site loop of the serpin SCCA1 is essential for cysteine proteinase inhibition

Charles Schick, Dieter Brömme, Allison J. Bartuski, Yoshiki Uemura, Norman M. Schechter, Gary A. Silverman

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


The high-molecular-weight serine proteinase inhibitors (serpins) are restricted, generally, to inhibiting proteinases of the serine mechanistic class. However, the viral serpin, cytokine response modifier A, and the human serpins, antichymotrypsin and squamous cell carcinoma antigen 1 (SCCA1), inhibit different members of the cysteine proteinase class. Although serpins employ a mobile reactive site loop (RSL) to bait and trap their target serine proteinases, the mechanism by which they inactivate cysteine proteinases is unknown. Our previous studies suggest that SCCA1 inhibits papain-like cysteine proteinases in a manner similar to that observed for serpin-serine proteinase interactions. However, we could not preclude the possibility of an inhibitory mechanism that did not require the serpin RSL. To test this possibility, we employed site-directed mutagenesis to alter the different residues within the RSL. Mutations to either the hinge or the variable region of the RSL abolished inhibitory activity. Moreover, RSL swaps between SCCA1 and the nearly identical serpin, SCCA2 (an inhibitor of chymotrypsin-like serine proteinases), reversed their target specificities. Thus, there were no unique motifs within the framework of SCCA1 that independently accounted for cysteine proteinase inhibitory activity. Collectively, these data suggested that the sequence and mobility of the RSL of SCCA1 are essential for cysteine proteinase inhibition and that serpins are likely to utilize a common RSL- dependent mechanism to inhibit both serine and cysteine proteinases.

Original languageEnglish
Pages (from-to)13465-13470
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number23
StatePublished - 10 Nov 1998


Dive into the research topics of 'The reactive site loop of the serpin SCCA1 is essential for cysteine proteinase inhibition'. Together they form a unique fingerprint.

Cite this