Channel forming activity of the perforin N-terminus and an a-helical region homologous with complement C9

ORCiD

David M. Ojcius: 0000-0003-1461-4495

Department

Biomedical Sciences

Document Type

Article

Publication Title

Biochemistry

ISSN

0006-2960

Volume

31

Issue

21

DOI

10.1021/bi00136a015

First Page

5017

Last Page

5021

Publication Date

6-1-1992

Abstract

Cytolytic lymphocytes are endowed with a pore-forming protein called perforin. Recently, a cytolytic domain was located in the first 34 residues of the perforin N-terminus. It has been proposed that the first 19 residues are composed of a 3-domain structure including a putative amphipathic β-sheet and that the 19 residues are sufficient for cytolytic activity. This model has now been tested by synthesizing peptides covering different portions of the N-terminus, and testing their ability to lyse lipid vesicles or increase the conductance of lipid bilayers or plasma membranes. It was found that the putative β-sheet is indispensable for lytic activity and that the first 19 residues of the N-terminus are required for optimal lytic activity but that shorter peptides, containing only 16 residues, can form pores in lipid bilayers and cell membranes. A putative amphipathic α-helix from the central portion of perforin, homologous to complement C9, is nonlytic to lipid vesicles, but it can form pores in lipid bilayers. Taken together, these results support the model that the perforin N-terminus is important in initial pore formation and that the putative α-helical domain may be involved in subsequent perforin polymerization into large pores.

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