Conformational changes in serpins: I. The native and cleaved conformations of α1-Antitrypsin

James C. Whisstock, Richard Skinner, Robin W. Carrell, Arthur Lesk

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

The serpins (SERine Proteinase INhibitors) are a family of proteins with important physiological roles, including but not limited to the inhibition of chymotrypsin-like serine proteinases. The inhibitory mechanism involves a large conformational change known as the S → R (stressed → relaxed) transition. The largest structural differences occur in a region around the scissile bond called the reactive centre loop: In the native (S) state, the reactive centre is exposed, and is free to interact with proteinases. In inhibitory serpins, in the cleaved (R) state the reactive centre loop forms an additional strand within the β-sheet. The latent state is an uncleaved state in which the intact reactive centre loop is integrated into the A sheet as in the cleaved form, to give an alternative R state. The serpin structures illustrate detailed control of conformation within a single protein. Serpins are also an unusual family of proteins in which homologues have native states with different folding topologies. Determination of the structures of inhibitory serpins in multiple conformational states permits a detailed analysis of the mechanism of the S → R transition, and of the way in which a single sequence can form two stabilised states of different topology. Here we compare the conformations of α1-antitrypsin in native and cleaved states. Many protein conformational changes involve relative motions of large rigid subunits. We determine the rigid subunits of α1-antitrypsin and analyse the changes in their relative position and orientation. Knowing that the conformational change is initiated by cleavage at the reactive centre, we describe a mechanism of the S → R transition as a logical sequence of mechanical effects, even though the transition likely proceeds in a concerted manner. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)651-665
Number of pages15
JournalJournal of Molecular Biology
Volume295
Issue number3
DOIs
StatePublished - Jan 21 2000

Fingerprint

Serine Proteinase Inhibitors
Proteins
Serpins
Chymotrypsin
Serine Proteases
Peptide Hydrolases
Escherichia coli periplasmic proteinase

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

Cite this

Whisstock, James C. ; Skinner, Richard ; Carrell, Robin W. ; Lesk, Arthur. / Conformational changes in serpins : I. The native and cleaved conformations of α1-Antitrypsin. In: Journal of Molecular Biology. 2000 ; Vol. 295, No. 3. pp. 651-665.
@article{a453d5136dba41b89ee7266845c3a804,
title = "Conformational changes in serpins: I. The native and cleaved conformations of α1-Antitrypsin",
abstract = "The serpins (SERine Proteinase INhibitors) are a family of proteins with important physiological roles, including but not limited to the inhibition of chymotrypsin-like serine proteinases. The inhibitory mechanism involves a large conformational change known as the S → R (stressed → relaxed) transition. The largest structural differences occur in a region around the scissile bond called the reactive centre loop: In the native (S) state, the reactive centre is exposed, and is free to interact with proteinases. In inhibitory serpins, in the cleaved (R) state the reactive centre loop forms an additional strand within the β-sheet. The latent state is an uncleaved state in which the intact reactive centre loop is integrated into the A sheet as in the cleaved form, to give an alternative R state. The serpin structures illustrate detailed control of conformation within a single protein. Serpins are also an unusual family of proteins in which homologues have native states with different folding topologies. Determination of the structures of inhibitory serpins in multiple conformational states permits a detailed analysis of the mechanism of the S → R transition, and of the way in which a single sequence can form two stabilised states of different topology. Here we compare the conformations of α1-antitrypsin in native and cleaved states. Many protein conformational changes involve relative motions of large rigid subunits. We determine the rigid subunits of α1-antitrypsin and analyse the changes in their relative position and orientation. Knowing that the conformational change is initiated by cleavage at the reactive centre, we describe a mechanism of the S → R transition as a logical sequence of mechanical effects, even though the transition likely proceeds in a concerted manner. (C) 2000 Academic Press.",
author = "Whisstock, {James C.} and Richard Skinner and Carrell, {Robin W.} and Arthur Lesk",
year = "2000",
month = "1",
day = "21",
doi = "10.1006/jmbi.1999.3375",
language = "English (US)",
volume = "295",
pages = "651--665",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
publisher = "Academic Press Inc.",
number = "3",

}

Conformational changes in serpins : I. The native and cleaved conformations of α1-Antitrypsin. / Whisstock, James C.; Skinner, Richard; Carrell, Robin W.; Lesk, Arthur.

In: Journal of Molecular Biology, Vol. 295, No. 3, 21.01.2000, p. 651-665.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Conformational changes in serpins

T2 - I. The native and cleaved conformations of α1-Antitrypsin

AU - Whisstock, James C.

AU - Skinner, Richard

AU - Carrell, Robin W.

AU - Lesk, Arthur

PY - 2000/1/21

Y1 - 2000/1/21

N2 - The serpins (SERine Proteinase INhibitors) are a family of proteins with important physiological roles, including but not limited to the inhibition of chymotrypsin-like serine proteinases. The inhibitory mechanism involves a large conformational change known as the S → R (stressed → relaxed) transition. The largest structural differences occur in a region around the scissile bond called the reactive centre loop: In the native (S) state, the reactive centre is exposed, and is free to interact with proteinases. In inhibitory serpins, in the cleaved (R) state the reactive centre loop forms an additional strand within the β-sheet. The latent state is an uncleaved state in which the intact reactive centre loop is integrated into the A sheet as in the cleaved form, to give an alternative R state. The serpin structures illustrate detailed control of conformation within a single protein. Serpins are also an unusual family of proteins in which homologues have native states with different folding topologies. Determination of the structures of inhibitory serpins in multiple conformational states permits a detailed analysis of the mechanism of the S → R transition, and of the way in which a single sequence can form two stabilised states of different topology. Here we compare the conformations of α1-antitrypsin in native and cleaved states. Many protein conformational changes involve relative motions of large rigid subunits. We determine the rigid subunits of α1-antitrypsin and analyse the changes in their relative position and orientation. Knowing that the conformational change is initiated by cleavage at the reactive centre, we describe a mechanism of the S → R transition as a logical sequence of mechanical effects, even though the transition likely proceeds in a concerted manner. (C) 2000 Academic Press.

AB - The serpins (SERine Proteinase INhibitors) are a family of proteins with important physiological roles, including but not limited to the inhibition of chymotrypsin-like serine proteinases. The inhibitory mechanism involves a large conformational change known as the S → R (stressed → relaxed) transition. The largest structural differences occur in a region around the scissile bond called the reactive centre loop: In the native (S) state, the reactive centre is exposed, and is free to interact with proteinases. In inhibitory serpins, in the cleaved (R) state the reactive centre loop forms an additional strand within the β-sheet. The latent state is an uncleaved state in which the intact reactive centre loop is integrated into the A sheet as in the cleaved form, to give an alternative R state. The serpin structures illustrate detailed control of conformation within a single protein. Serpins are also an unusual family of proteins in which homologues have native states with different folding topologies. Determination of the structures of inhibitory serpins in multiple conformational states permits a detailed analysis of the mechanism of the S → R transition, and of the way in which a single sequence can form two stabilised states of different topology. Here we compare the conformations of α1-antitrypsin in native and cleaved states. Many protein conformational changes involve relative motions of large rigid subunits. We determine the rigid subunits of α1-antitrypsin and analyse the changes in their relative position and orientation. Knowing that the conformational change is initiated by cleavage at the reactive centre, we describe a mechanism of the S → R transition as a logical sequence of mechanical effects, even though the transition likely proceeds in a concerted manner. (C) 2000 Academic Press.

UR - http://www.scopus.com/inward/record.url?scp=0034695402&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034695402&partnerID=8YFLogxK

U2 - 10.1006/jmbi.1999.3375

DO - 10.1006/jmbi.1999.3375

M3 - Article

C2 - 10623554

AN - SCOPUS:0034695402

VL - 295

SP - 651

EP - 665

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 0022-2836

IS - 3

ER -