The role of conserved residues of chagasin in the inhibition of cysteine peptidases

Flavia C.G. Dos Reis; Brian O. Smith; Camila C. Santos; Tatiana F.R. Costa; Julio Scharfstein; Graham H. Coombs; Jeremy C. Mottram; Ana Paula C.A. Lima

doi:10.1016/j.febslet.2008.01.008

The role of conserved residues of chagasin in the inhibition of cysteine peptidases

Flavia C.G. Dos Reis, Brian O. Smith, Camila C. Santos, Tatiana F.R. Costa, Julio Scharfstein, Graham H. Coombs, Jeremy C. Mottram, Ana Paula C.A. Lima

Strathclyde Institute Of Pharmacy And Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

23 Citations (Scopus)

Abstract

We have evaluated the roles of key amino acids to the action of the natural inhibitor chagasin of papain-family cysteine peptidases. A W93A substitution decreased inhibitor affinity for human cathepsin L 100-fold, while substitutions of T31 resulted in 10-100-fold increases in the Ki for cruzipain of Trypanosoma cruzi. A T31A/T32A double mutant had increased affinity for cathepsin L but not for cruzipain, while the T31-T32 deletion drastically affected inhibition of both human and parasite peptidases. These differential effects reflect the occurrence of direct interactions between chagasin and helix 8 of cathepsin L, interactions that do not occur with cruzipain.

Original language	English
Pages (from-to)	485-490
Number of pages	5
Journal	FEBS Letters
Volume	582
Issue number	4
DOIs	https://doi.org/10.1016/j.febslet.2008.01.008
Publication status	Published - 20 Feb 2008

Keywords

chagasin
cysteine peptidase
inhibitor
mutant
Trypanosoma

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10.1016/j.febslet.2008.01.008

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title = "The role of conserved residues of chagasin in the inhibition of cysteine peptidases",

abstract = "We have evaluated the roles of key amino acids to the action of the natural inhibitor chagasin of papain-family cysteine peptidases. A W93A substitution decreased inhibitor affinity for human cathepsin L 100-fold, while substitutions of T31 resulted in 10-100-fold increases in the Ki for cruzipain of Trypanosoma cruzi. A T31A/T32A double mutant had increased affinity for cathepsin L but not for cruzipain, while the T31-T32 deletion drastically affected inhibition of both human and parasite peptidases. These differential effects reflect the occurrence of direct interactions between chagasin and helix 8 of cathepsin L, interactions that do not occur with cruzipain.",

keywords = "chagasin, cysteine peptidase, inhibitor, mutant, Trypanosoma",

author = "{Dos Reis}, {Flavia C.G.} and Smith, {Brian O.} and Santos, {Camila C.} and Costa, {Tatiana F.R.} and Julio Scharfstein and Coombs, {Graham H.} and Mottram, {Jeremy C.} and Lima, {Ana Paula C.A.}",

note = "Strathprints' policy is to record up to 8 authors per publication, plus any additional authors based at the University of Strathclyde. More authors may be listed on the official publication than appear in the Strathprints' record.",

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doi = "10.1016/j.febslet.2008.01.008",

language = "English",

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pages = "485--490",

journal = "FEBS Letters",

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T1 - The role of conserved residues of chagasin in the inhibition of cysteine peptidases

AU - Dos Reis, Flavia C.G.

AU - Smith, Brian O.

AU - Santos, Camila C.

AU - Costa, Tatiana F.R.

AU - Scharfstein, Julio

AU - Coombs, Graham H.

AU - Mottram, Jeremy C.

AU - Lima, Ana Paula C.A.

N1 - Strathprints' policy is to record up to 8 authors per publication, plus any additional authors based at the University of Strathclyde. More authors may be listed on the official publication than appear in the Strathprints' record.

PY - 2008/2/20

Y1 - 2008/2/20

N2 - We have evaluated the roles of key amino acids to the action of the natural inhibitor chagasin of papain-family cysteine peptidases. A W93A substitution decreased inhibitor affinity for human cathepsin L 100-fold, while substitutions of T31 resulted in 10-100-fold increases in the Ki for cruzipain of Trypanosoma cruzi. A T31A/T32A double mutant had increased affinity for cathepsin L but not for cruzipain, while the T31-T32 deletion drastically affected inhibition of both human and parasite peptidases. These differential effects reflect the occurrence of direct interactions between chagasin and helix 8 of cathepsin L, interactions that do not occur with cruzipain.

AB - We have evaluated the roles of key amino acids to the action of the natural inhibitor chagasin of papain-family cysteine peptidases. A W93A substitution decreased inhibitor affinity for human cathepsin L 100-fold, while substitutions of T31 resulted in 10-100-fold increases in the Ki for cruzipain of Trypanosoma cruzi. A T31A/T32A double mutant had increased affinity for cathepsin L but not for cruzipain, while the T31-T32 deletion drastically affected inhibition of both human and parasite peptidases. These differential effects reflect the occurrence of direct interactions between chagasin and helix 8 of cathepsin L, interactions that do not occur with cruzipain.

KW - chagasin

KW - cysteine peptidase

KW - inhibitor

KW - mutant

KW - Trypanosoma

UR - http://dx.doi.org/10.1016/j.febslet.2008.01.008

U2 - 10.1016/j.febslet.2008.01.008

DO - 10.1016/j.febslet.2008.01.008

M3 - Article

SN - 0014-5793

VL - 582

SP - 485

EP - 490

JO - FEBS Letters

JF - FEBS Letters

IS - 4

ER -

The role of conserved residues of chagasin in the inhibition of cysteine peptidases

Abstract

Keywords

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