PMID- 28504839
OWN - NLM
STAT- MEDLINE
DCOM- 20171002
LR  - 20221012
IS  - 1742-4658 (Electronic)
IS  - 1742-464X (Print)
IS  - 1742-464X (Linking)
VI  - 284
IP  - 13
DP  - 2017 Jul
TI  - The pathological Trento variant of alpha-1-antitrypsin (E75V) shows nonclassical 
      behaviour during polymerization.
PG  - 2110-2126
LID - 10.1111/febs.14111 [doi]
AB  - Severe alpha-1-antitrypsin deficiency (AATD) is most frequently associated with 
      the alpha-1-antitrypsin (AAT) Z variant (E342K). ZZ homozygotes exhibit 
      accumulation of AAT as polymers in the endoplasmic reticulum of hepatocytes. This 
      protein deposition can lead to liver disease, with the resulting low circulating 
      levels of AAT predisposing to early-onset emphysema due to dysregulation of 
      elastinolytic activity in the lungs. An increasing number of rare AAT alleles 
      have been identified in patients with severe AATD, typically in combination with 
      the Z allele. Here we report a new mutation (E75V) in a patient with severe 
      plasma deficiency, which we designate Trento. In contrast to the Z mutant, Trento 
      AAT was secreted efficiently when expressed in cellular models but showed 
      compromised conformational stability. Polyacrylamide gel electrophoresis (PAGE) 
      and ELISA-based analyses of the secreted protein revealed the presence of 
      oligomeric species with electrophoretic and immunorecognition profiles different 
      from those of Z and S (E264V) AAT polymers, including reduced recognition by 
      conformational monoclonal antibodies 2C1 and 4B12. This altered recognition was 
      not due to direct effects on the epitope of the 2C1 monoclonal antibody which we 
      localized between helices E and F. Structural analyses indicate the likely basis 
      for polymer formation is the loss of a highly conserved stabilizing interaction 
      between helix C and the posthelix I loop. These results highlight this region as 
      important for maintaining native state stability and, when compromised, results 
      in the formation of pathological polymers that are different from those produced 
      by Z and S AAT.
CI  - (c) 2017 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf 
      of Federation of European Biochemical Societies.
FAU - Miranda, Elena
AU  - Miranda E
AUID- ORCID: 0000-0002-0586-8795
AD  - Department of Biology and Biotechnologies 'Charles Darwin', Sapienza University 
      of Rome, Italy.
FAU - Ferrarotti, Ilaria
AU  - Ferrarotti I
AD  - Department of Internal Medicine and Therapeutics, Pneumology Unit, University of 
      Pavia, Italy.
FAU - Berardelli, Romina
AU  - Berardelli R
AD  - Department of Molecular and Translational Medicine, University of Brescia, Italy.
FAU - Laffranchi, Mattia
AU  - Laffranchi M
AD  - Department of Molecular and Translational Medicine, University of Brescia, Italy.
FAU - Cerea, Marta
AU  - Cerea M
AD  - Department of Biology and Biotechnologies 'Charles Darwin', Sapienza University 
      of Rome, Italy.
AD  - Department of Molecular and Translational Medicine, University of Brescia, Italy.
FAU - Gangemi, Fabrizio
AU  - Gangemi F
AD  - Department of Molecular and Translational Medicine, University of Brescia, Italy.
FAU - Haq, Imran
AU  - Haq I
AD  - UCL Respiratory and the Institute of Structural and Molecular Biology, University 
      College London, UK.
FAU - Ottaviani, Stefania
AU  - Ottaviani S
AD  - Center for Diagnosis of Inherited Alpha 1-Antitrypsin Deficiency, Pneumology 
      Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
FAU - Lomas, David A
AU  - Lomas DA
AD  - UCL Respiratory and the Institute of Structural and Molecular Biology, University 
      College London, UK.
FAU - Irving, James A
AU  - Irving JA
AUID- ORCID: 0000-0003-3204-6356
AD  - UCL Respiratory and the Institute of Structural and Molecular Biology, University 
      College London, UK.
FAU - Fra, Annamaria
AU  - Fra A
AUID- ORCID: 0000-0002-4327-3004
AD  - Department of Molecular and Translational Medicine, University of Brescia, Italy.
LA  - eng
GR  - MR/N024842/1/MRC_/Medical Research Council/United Kingdom
GR  - DH_/Department of Health/United Kingdom
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170608
PL  - England
TA  - FEBS J
JT  - The FEBS journal
JID - 101229646
RN  - 0 (SERPINA1 protein, human)
RN  - 0 (alpha 1-Antitrypsin)
RN  - alpha-1-Antitrypsin Deficiency, Autosomal Recessive
SB  - IM
MH  - Electrophoresis, Polyacrylamide Gel
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Genetic Predisposition to Disease/*genetics
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Molecular Dynamics Simulation
MH  - *Mutation
MH  - Polymerization
MH  - Protein Conformation
MH  - alpha 1-Antitrypsin/chemistry/*genetics/metabolism
MH  - alpha 1-Antitrypsin Deficiency/blood/*genetics/metabolism
PMC - PMC5518210
OTO - NOTNLM
OT  - alpha-1-antitrypsin deficiency
OT  - emphysema
OT  - misfolding diseases
OT  - serpin polymers
OT  - serpins
EDAT- 2017/05/16 06:00
MHDA- 2017/10/03 06:00
PMCR- 2017/07/20
CRDT- 2017/05/16 06:00
PHST- 2017/02/13 00:00 [received]
PHST- 2017/04/26 00:00 [revised]
PHST- 2017/05/12 00:00 [accepted]
PHST- 2017/05/16 06:00 [pubmed]
PHST- 2017/10/03 06:00 [medline]
PHST- 2017/05/16 06:00 [entrez]
PHST- 2017/07/20 00:00 [pmc-release]
AID - FEBS14111 [pii]
AID - 10.1111/febs.14111 [doi]
PST - ppublish
SO  - FEBS J. 2017 Jul;284(13):2110-2126. doi: 10.1111/febs.14111. Epub 2017 Jun 8.