NDLI: The Z Mutation Alters the Global Structural Dynamics of α1-Antitrypsin

Content Provider	PubMed Central
Author	Hughes, Victoria A. Robert, Meklemburg Bottomley, Stephen P. Wintrode, Patrick L.
Editor	Rezaei, Human
Copyright Year	2014
Abstract	α1-Antitrypsin (α1AT) deficiency, the most common serpinopathy, results in both emphysema and liver disease. Over 90% of all clinical cases of α1AT deficiency are caused by the Z variant in which Glu342, located at the top of s5A, is replaced by a Lys which results in polymerization both in vivo and in vitro. The Glu342Lys mutation removes a salt bridge and a hydrogen bond but does not effect the thermodynamic stability of Z α1AT compared to the wild type protein, M α1AT, and so it is unclear why Z α1AT has an increased polymerization propensity. We speculated that the loss of these interactions would make the native state of Z α1AT more dynamic than M α1AT and that this change renders the protein more polymerization prone. We have used hydrogen/deuterium exchange combined with mass spectrometry (HXMS) to determine the structural and dynamic differences between native Z and M α1AT to reveal the molecular basis of Z α1AT polymerization. Our HXMS data shows that the Z mutation significantly perturbs the region around the site of mutation. Strikingly the Z mutation also alters the dynamics of regions distant to the mutation such as the B, D and I helices and specific regions of each β-sheet. These changes in global dynamics may lead to an increase in the likelihood of Z α1AT sampling a polymerogenic structure thereby causing disease.
Related Links	http://dx.doi.org/10.1371/journal.pone.0102617
Starting Page	102617
File Format	PDF
ISSN	19326203
e-ISSN	19326203
Journal	PLoS ONE
Issue Number	9
Volume Number	9
Language	English
Publisher	Public Library of Science
Publisher Date	2014-09-01
Access Restriction	Open
Rights Holder	Public Library of Science
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Agricultural and Biological Sciences(all) Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

ATZ11 Recognizes Not Only Z-α1-Antitrypsin-Polymers and Complexed Forms of Non-Z-α1-Antitrypsin but Also the von Willebrand Factor

Automated High-Content Live Animal Drug Screening Using C. elegans Expressing the Aggregation Prone Serpin α1-antitrypsin Z

In Silico Assessment of Potential Druggable Pockets on the Surface of α1-Antitrypsin Conformers

Discovery of an Inhibitor of Z-Alpha1 Antitrypsin Polymerization

The Roles of Helix I and Strand 5A in the Folding, Function and Misfolding of α1-Antitrypsin

Longer Telomere Length in COPD Patients with α1-Antitrypsin Deficiency Independent of Lung Function

A Novel SERPINA1 Mutation Causing Serum Alpha1-Antitrypsin Deficiency

Unconscious Local Motion Alters Global Image Speed

Obstructive Sleep Apnea Alters Sleep Stage Transition Dynamics

The Z Mutation Alters the Global Structural Dynamics of α1-Antitrypsin

Similar Documents

ATZ11 Recognizes Not Only Z-α1-Antitrypsin-Polymers and Complexed Forms of Non-Z-α1-Antitrypsin but Also the von Willebrand Factor

Automated High-Content Live Animal Drug Screening Using C. elegans Expressing the Aggregation Prone Serpin α1-antitrypsin Z

In Silico Assessment of Potential Druggable Pockets on the Surface of α1-Antitrypsin Conformers

Discovery of an Inhibitor of Z-Alpha1 Antitrypsin Polymerization

The Roles of Helix I and Strand 5A in the Folding, Function and Misfolding of α1-Antitrypsin

Longer Telomere Length in COPD Patients with α1-Antitrypsin Deficiency Independent of Lung Function

A Novel SERPINA1 Mutation Causing Serum Alpha1-Antitrypsin Deficiency

Unconscious Local Motion Alters Global Image Speed

Obstructive Sleep Apnea Alters Sleep Stage Transition Dynamics

The Z Mutation Alters the Global Structural Dynamics of α1-Antitrypsin