PMID- 30299960
OWN - NLM
STAT- MEDLINE
DCOM- 20191024
LR  - 20191024
IS  - 1520-5207 (Electronic)
IS  - 1520-5207 (Linking)
VI  - 122
IP  - 43
DP  - 2018 Nov 1
TI  - Zinc-Induced Conformational Transitions in Human Islet Amyloid Polypeptide and 
      Their Role in the Inhibition of Amyloidosis.
PG  - 9852-9859
LID - 10.1021/acs.jpcb.8b06206 [doi]
AB  - Type-2 diabetes mellitus (T2DM) is a disease hallmarked by improper homeostasis 
      within the islets of Langerhans of the pancreas. The most critical species 
      affected is insulin, which is produced by the beta-cells of the islets, but there 
      are a number of other species copackaged and cosecreted within the insulin 
      granules. This includes zinc, which exists in high (millimolar) concentrations 
      within the beta-cells, and islet amyloid polypeptide (IAPP), which is an amyloid 
      peptide thought to induce beta-cell apoptosis through self-association into toxic 
      amyloid oligomers. Zinc is essential in the packaging of crystalline insulin 
      within the vesicles but it can also bind and interact with IAPP. This implies a 
      complex relationship between all three species and diabetes, particularly in the 
      structure and function of toxic IAPP aggregates. Atypical (low or high) 
      concentrations of zinc generally appear to correlate with increased hIAPP 
      aggregation, whereas physiological zinc concentrations have an inhibitory effect. 
      To better understand how zinc ions alter the monomer and oligomer structure of 
      hIAPP in vitro, we employ a combination of ion mobility mass spectrometry and 
      atomic force microscopy. We observe an increase in the extended beta-hairpin 
      conformation of hIAPP when it is bound to zinc. With sufficiently low 
      concentrations of zinc this could result in an association site for zinc-free 
      hIAPP, promoting amyloid aggregation. At high zinc concentrations, we see the 
      appearance of a secondary zinc association site whose coordination could account 
      for the loss of inhibition at high zinc concentrations. Generally, it appears 
      that zinc preferentially stabilizes the beta-hairpin conformation of hIAPP and the 
      population of zinc-bound hIAPP in solution determines what effect this has on 
      amyloid aggregation.
FAU - Ilitchev, Alexandre I
AU  - Ilitchev AI
AUID- ORCID: 0000-0002-1503-4217
AD  - Department of Chemistry and Biochemistry , University of California , Santa 
      Barbara , California 93106 , United States.
FAU - Giammona, Maxwell J
AU  - Giammona MJ
AD  - Department of Chemistry and Biochemistry , University of California , Santa 
      Barbara , California 93106 , United States.
FAU - Schwarze, Jurgen N
AU  - Schwarze JN
AD  - Department of Chemistry and Biochemistry , University of California , Santa 
      Barbara , California 93106 , United States.
FAU - Buratto, Steven K
AU  - Buratto SK
AD  - Department of Chemistry and Biochemistry , University of California , Santa 
      Barbara , California 93106 , United States.
FAU - Bowers, Michael T
AU  - Bowers MT
AD  - Department of Chemistry and Biochemistry , University of California , Santa 
      Barbara , California 93106 , United States.
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20181018
PL  - United States
TA  - J Phys Chem B
JT  - The journal of physical chemistry. B
JID - 101157530
RN  - 0 (Amyloid)
RN  - 0 (Islet Amyloid Polypeptide)
RN  - J41CSQ7QDS (Zinc)
SB  - IM
MH  - Amyloid/*metabolism
MH  - Humans
MH  - Islet Amyloid Polypeptide/*chemistry/metabolism
MH  - Mass Spectrometry
MH  - Microscopy, Atomic Force
MH  - Protein Conformation, beta-Strand
MH  - Zinc/*chemistry
EDAT- 2018/10/10 06:00
MHDA- 2019/10/28 06:00
CRDT- 2018/10/10 06:00
PHST- 2018/10/10 06:00 [pubmed]
PHST- 2019/10/28 06:00 [medline]
PHST- 2018/10/10 06:00 [entrez]
AID - 10.1021/acs.jpcb.8b06206 [doi]
PST - ppublish
SO  - J Phys Chem B. 2018 Nov 1;122(43):9852-9859. doi: 10.1021/acs.jpcb.8b06206. Epub 
      2018 Oct 18.