PMID- 31442763
OWN - NLM
STAT- MEDLINE
DCOM- 20191206
LR  - 20191217
IS  - 1873-4200 (Electronic)
IS  - 0301-4622 (Linking)
VI  - 254
DP  - 2019 Nov
TI  - The pressure and temperature perturbation approach reveals a whole variety of 
      conformational substates of amyloidogenic hIAPP monitored by 2D NMR spectroscopy.
PG  - 106239
LID - S0301-4622(19)30274-1 [pii]
LID - 10.1016/j.bpc.2019.106239 [doi]
AB  - The intrinsically disordered human islet amyloid polypeptide (hIAPP) is a 37 
      amino acid peptide hormone that is secreted by pancreatic beta cells along with 
      glucagon and insulin. The glucose metabolism of humans is regulated by a balanced 
      ratio of insulin and hIAPP. The disturbance of this balance can result in the 
      development of type-2 diabetes mellitus (T2DM), whose pathogeny is associated by 
      self-assembly induced aggregation and amyloid deposits of hIAPP into nanofibrils. 
      Here, we report pressure- and temperature-induced changes of NMR chemical shifts 
      of monomeric hIAPP in bulk solution to elucidate the contribution of 
      conformational substates in a residue-specific manner in their role as molecular 
      determinants for the initial self-assembly. The comparison with a similar 
      peptide, the Alzheimer peptide Abeta(1-40), which is leading to self-assembly 
      induced aggregation and amyloid deposits as well, reveals that in both peptides 
      highly homologous areas exist (Q10-‍L16 and N21-L27 in hIAPP and Q15-A21 and 
      S26-I32 in Abeta). The N-terminal area of hIAPP around amino acid residues 3-20 
      displays large differences in pressure sensitivity compared to Abeta, pinpointing to 
      a different structural ensemble in this sequence element which is of helical 
      origin in hIAPP. Knowledge of the structural nature of the highly amyloidogenic 
      hIAPP and the differences with respect to the conformational ensemble of Abeta(1-40) 
      will help to identify molecular determinants of self-assembly as well as 
      cross-seeded assembly initiated aggregation and help facilitate the rational 
      design of drugs for therapeutic use.
CI  - Copyright (c) 2019. Published by Elsevier B.V.
FAU - Beck Erlach, Markus
AU  - Beck Erlach M
AD  - Institute of Biophysics and Physical Biochemistry, Center for Magnetic Resonance 
      in Chemistry and Biomedicine, University of Regensburg, Universitatsstr. 31, 
      93053 Regensburg, Germany.
FAU - Kalbitzer, Hans Robert
AU  - Kalbitzer HR
AD  - Institute of Biophysics and Physical Biochemistry, Center for Magnetic Resonance 
      in Chemistry and Biomedicine, University of Regensburg, Universitatsstr. 31, 
      93053 Regensburg, Germany.
FAU - Winter, Roland
AU  - Winter R
AD  - Physical Chemistry I- Biophysical Chemistry, Technical University Dortmund, 
      Otto-Hahn-Str. 4a, 44227 Dortmund, Germany.
FAU - Kremer, Werner
AU  - Kremer W
AD  - Institute of Biophysics and Physical Biochemistry, Center for Magnetic Resonance 
      in Chemistry and Biomedicine, University of Regensburg, Universitatsstr. 31, 
      93053 Regensburg, Germany. Electronic address: werner.kremer@ur.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190730
PL  - Netherlands
TA  - Biophys Chem
JT  - Biophysical chemistry
JID - 0403171
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Islet Amyloid Polypeptide)
RN  - 0 (Peptide Fragments)
RN  - 0 (amyloid beta-protein (1-40))
SB  - IM
MH  - Amino Acid Sequence
MH  - Amyloid beta-Peptides/chemistry/metabolism
MH  - Humans
MH  - Islet Amyloid Polypeptide/*chemistry/metabolism
MH  - Molecular Dynamics Simulation
MH  - *Nuclear Magnetic Resonance, Biomolecular
MH  - Peptide Fragments/chemistry/metabolism
MH  - Pressure
MH  - Protein Conformation
MH  - Substrate Specificity
MH  - Temperature
OTO - NOTNLM
OT  - Amylin
OT  - Amyloid
OT  - Fibrils
OT  - IAPP
OT  - NMR
EDAT- 2019/08/24 06:00
MHDA- 2019/12/18 06:00
CRDT- 2019/08/24 06:00
PHST- 2019/06/19 00:00 [received]
PHST- 2019/07/26 00:00 [revised]
PHST- 2019/07/26 00:00 [accepted]
PHST- 2019/08/24 06:00 [pubmed]
PHST- 2019/12/18 06:00 [medline]
PHST- 2019/08/24 06:00 [entrez]
AID - S0301-4622(19)30274-1 [pii]
AID - 10.1016/j.bpc.2019.106239 [doi]
PST - ppublish
SO  - Biophys Chem. 2019 Nov;254:106239. doi: 10.1016/j.bpc.2019.106239. Epub 2019 Jul 
      30.