Three-dimensional structure and orientation of rat islet amyloid polypeptide protein in a membrane environment by solution NMR spectroscopy.
Islet amyloid polypeptide (IAPP or amylin) is a 37-residue peptide hormone associated with glucose metabolism that is cosecreted with insulin by beta-cells in the pancreas. Since human IAPP is a highly amyloidogenic peptide, it has been suggested that the formation of IAPP amyloid fibers is responsible for the death of beta-cells during the early stages of type II diabetes. It has been hypothesized that transient membrane-bound alpha-helical structures of human IAPP are precursors to the formation of these amyloid deposits. On the other hand, rat IAPP forms transient alpha-helical structures but does not progress further to form amyloid fibrils. To understand the nature of this intermediate state and the difference in toxicity between the rat and human versions of IAPP, we have solved the high-resolution structure of rat IAPP in the membrane-mimicking detergent micelles composed of dodecylphosphocholine. The structure is characterized by a helical region spanning the residues A5 to S23 and a disordered C-terminus. A distortion in the helix is seen at R18 and S19 that may be involved in receptor binding. Paramagnetic quenching NMR experiments indicate that rat IAPP is bound on the surface of the micelle, in agreement with other nontoxic forms of IAPP. A comparison to the detergent-bound structures of other IAPP variants indicates that the N-terminal region may play a crucial role in the self-association and toxicity of IAPP by controlling access to the putative dimerization interface on the hydrophobic face of the amphipathic helix.
Nanga
Ravi Prakash Reddy
RP
Department of Chemistry and Biophysics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Brender
Jeffrey R
JR
Xu
Jiadi
J
Hartman
Kevin
K
Subramanian
Vivekanandan
V
Ramamoorthy
Ayyalusamy
A
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D058228:Islet Amyloid Polypeptide; D008566:Membranes / Q000737:chemistry; D008823:Micelles; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000737:chemistry; D017433:Protein Structure, Secondary; D051381:Rats; D012996:Solutions
D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D008823:Micelles; D012996:Solutions; D010767:Phosphorylcholine; C028810:dodecylphosphocholine