Deficiency mutations of α1-antitrypsin differentially affect folding, function and polymerisation

Imran Haq; James A Irving; Aarash Saleh; Louis Dron; John R. Hurst; Gemma Regan-Mochrie; Neda Motamedi-Shad; David A. Lomas; Bibekbrata Gooptu

doi:10.1165/rcmb.2015-0154OC

Deficiency mutations of α₁-antitrypsin differentially affect folding, function and polymerisation

Imran Haq, James A Irving, Aarash Saleh, Louis Dron, John R. Hurst, Gemma Regan-Mochrie, Neda Motamedi-Shad, David A. Lomas, Bibekbrata Gooptu

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

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Abstract

Misfolding, polymerisation and defective secretion of functional α1-antitrypsin underlies the predisposition to severe liver and lung disease in α1-antitrypsin deficiency. We have identified a novel (Ala336Pro, Baghdad) deficiency variant and characterised it relative to the wild-type (M) and Glu342Lys (Z) alleles. The index case is a homozygous individual of consanguineous parentage, with levels of circulating α1-antitrypsin in the moderate deficiency range, but a biochemical phenotype that could not be classified by standard methods. The majority of the protein was present as functionally inactive polymer, and the remaining monomer was 37% active relative to the wild-type protein. These factors combined indicate a 85-95% functional deficiency, similar to that seen with ZZ homozygotes. Biochemical, biophysical and computational studies further defined the molecular basis of this deficiency. These demonstrated that native Ala336Pro α1-antitrypsin could populate the polymerogenic intermediate – and therefore polymerise – more readily than either wild-type α1-antitrypsin or the Z variant. In contrast, folding was far less impaired in Ala336Pro α1-antitrypsin than in the Z variant. The data are consistent with a disparate contribution by the ‘breach’ region and ‘shutter’ region of strand 5A to folding and to polymerisation mechanisms. Moreover, the findings demonstrate that in these variants, folding efficiency does not correlate directly with the tendency to polymerise in vitro or in vivo. They therefore differentiate generalised misfolding from polymerisation tendencies in missense variants of α1-antitrypsin. Clinically they further support the need to quantify loss-of-function in α1-antitrypsin deficiency to individualise patient care.

Original language	English
Number of pages	28
Journal	American Journal of Respiratory Cell and Molecular Biology
DOIs	https://doi.org/10.1165/rcmb.2015-0154OC
Publication status	Published - 19 Jun 2015

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Cite this

@article{fc08b791193d4b6593a7d98285afc4bb,

title = "Deficiency mutations of α1-antitrypsin differentially affect folding, function and polymerisation",

abstract = "Misfolding, polymerisation and defective secretion of functional α1-antitrypsin underlies the predisposition to severe liver and lung disease in α1-antitrypsin deficiency. We have identified a novel (Ala336Pro, Baghdad) deficiency variant and characterised it relative to the wild-type (M) and Glu342Lys (Z) alleles. The index case is a homozygous individual of consanguineous parentage, with levels of circulating α1-antitrypsin in the moderate deficiency range, but a biochemical phenotype that could not be classified by standard methods. The majority of the protein was present as functionally inactive polymer, and the remaining monomer was 37% active relative to the wild-type protein. These factors combined indicate a 85-95% functional deficiency, similar to that seen with ZZ homozygotes. Biochemical, biophysical and computational studies further defined the molecular basis of this deficiency. These demonstrated that native Ala336Pro α1-antitrypsin could populate the polymerogenic intermediate – and therefore polymerise – more readily than either wild-type α1-antitrypsin or the Z variant. In contrast, folding was far less impaired in Ala336Pro α1-antitrypsin than in the Z variant. The data are consistent with a disparate contribution by the {\textquoteleft}breach{\textquoteright} region and {\textquoteleft}shutter{\textquoteright} region of strand 5A to folding and to polymerisation mechanisms. Moreover, the findings demonstrate that in these variants, folding efficiency does not correlate directly with the tendency to polymerise in vitro or in vivo. They therefore differentiate generalised misfolding from polymerisation tendencies in missense variants of α1-antitrypsin. Clinically they further support the need to quantify loss-of-function in α1-antitrypsin deficiency to individualise patient care.",

author = "Imran Haq and Irving, {James A} and Aarash Saleh and Louis Dron and Hurst, {John R.} and Gemma Regan-Mochrie and Neda Motamedi-Shad and Lomas, {David A.} and Bibekbrata Gooptu",

year = "2015",

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doi = "10.1165/rcmb.2015-0154OC",

language = "English",

journal = "American Journal of Respiratory Cell and Molecular Biology",

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T1 - Deficiency mutations of α1-antitrypsin differentially affect folding, function and polymerisation

AU - Haq, Imran

AU - Irving, James A

AU - Saleh, Aarash

AU - Dron, Louis

AU - Hurst, John R.

AU - Regan-Mochrie, Gemma

AU - Motamedi-Shad, Neda

AU - Lomas, David A.

AU - Gooptu, Bibekbrata

PY - 2015/6/19

Y1 - 2015/6/19

N2 - Misfolding, polymerisation and defective secretion of functional α1-antitrypsin underlies the predisposition to severe liver and lung disease in α1-antitrypsin deficiency. We have identified a novel (Ala336Pro, Baghdad) deficiency variant and characterised it relative to the wild-type (M) and Glu342Lys (Z) alleles. The index case is a homozygous individual of consanguineous parentage, with levels of circulating α1-antitrypsin in the moderate deficiency range, but a biochemical phenotype that could not be classified by standard methods. The majority of the protein was present as functionally inactive polymer, and the remaining monomer was 37% active relative to the wild-type protein. These factors combined indicate a 85-95% functional deficiency, similar to that seen with ZZ homozygotes. Biochemical, biophysical and computational studies further defined the molecular basis of this deficiency. These demonstrated that native Ala336Pro α1-antitrypsin could populate the polymerogenic intermediate – and therefore polymerise – more readily than either wild-type α1-antitrypsin or the Z variant. In contrast, folding was far less impaired in Ala336Pro α1-antitrypsin than in the Z variant. The data are consistent with a disparate contribution by the ‘breach’ region and ‘shutter’ region of strand 5A to folding and to polymerisation mechanisms. Moreover, the findings demonstrate that in these variants, folding efficiency does not correlate directly with the tendency to polymerise in vitro or in vivo. They therefore differentiate generalised misfolding from polymerisation tendencies in missense variants of α1-antitrypsin. Clinically they further support the need to quantify loss-of-function in α1-antitrypsin deficiency to individualise patient care.

AB - Misfolding, polymerisation and defective secretion of functional α1-antitrypsin underlies the predisposition to severe liver and lung disease in α1-antitrypsin deficiency. We have identified a novel (Ala336Pro, Baghdad) deficiency variant and characterised it relative to the wild-type (M) and Glu342Lys (Z) alleles. The index case is a homozygous individual of consanguineous parentage, with levels of circulating α1-antitrypsin in the moderate deficiency range, but a biochemical phenotype that could not be classified by standard methods. The majority of the protein was present as functionally inactive polymer, and the remaining monomer was 37% active relative to the wild-type protein. These factors combined indicate a 85-95% functional deficiency, similar to that seen with ZZ homozygotes. Biochemical, biophysical and computational studies further defined the molecular basis of this deficiency. These demonstrated that native Ala336Pro α1-antitrypsin could populate the polymerogenic intermediate – and therefore polymerise – more readily than either wild-type α1-antitrypsin or the Z variant. In contrast, folding was far less impaired in Ala336Pro α1-antitrypsin than in the Z variant. The data are consistent with a disparate contribution by the ‘breach’ region and ‘shutter’ region of strand 5A to folding and to polymerisation mechanisms. Moreover, the findings demonstrate that in these variants, folding efficiency does not correlate directly with the tendency to polymerise in vitro or in vivo. They therefore differentiate generalised misfolding from polymerisation tendencies in missense variants of α1-antitrypsin. Clinically they further support the need to quantify loss-of-function in α1-antitrypsin deficiency to individualise patient care.

U2 - 10.1165/rcmb.2015-0154OC

DO - 10.1165/rcmb.2015-0154OC

M3 - Article

SN - 1044-1549

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology