Aggregation-induced conformation changes dictate islet amyloid polypeptide (IAPP) membrane affinity

Rawat, Anoop; Maity, Barun Kumar; Chandra, Bappaditya; Maiti, Sudipta

doi:10.1016/j.bbamem.2018.03.027

Cited by 23 publications

(30 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This data suggests that conversion from β-sheet in oligomer to loop in fibrils poses free energy barrier that in turn generates a lag phase in IAPP aggregation. A recent Fourier transform infrared (FTIR) and Raman spectroscopy study showed considerable α-helical content in early IAPP oligomers [103]. This study also suggested that such oligomers could have enhanced membrane affinity.…”

Section: Structures In Solutionmentioning

confidence: 62%

Membranes as modulators of amyloid protein misfolding and target of toxicity

Rawat

Langen

Varkey

2018

Biochimica et Biophysica Acta (BBA) - Biomembranes

Self Cite

View full text Add to dashboard Cite

Abnormal protein aggregation is a hallmark of various human diseases. α-Synuclein, a protein implicated in Parkinson's disease, is found in aggregated form within Lewy bodies that are characteristically observed in the brains of PD patients. Similarly, deposits of aggregated human islet amyloid polypeptide (IAPP) are found in the pancreatic islets in individuals with type 2 diabetes mellitus. Significant number of studies have focused on how monomeric, disaggregated proteins transition into various amyloid structures leading to identification of a vast number of aggregation promoting molecules and processes over the years. Inasmuch as these factors likely enhance the formation of toxic, misfolded species, they might act as risk factors in disease. Cellular membranes, and particularly certain lipids, are considered to be among the major players for aggregation of α-synuclein and IAPP, and membranes might also be the target of toxicity. Past studies have utilized an array of biophysical tools, both in vitro and in vivo, to expound the membrane-mediated aggregation. Here, we focus on membrane interaction of α-synuclein and IAPP, and how various kinds of membranes catalyze or modulate the aggregation of these proteins and how, in turn, these proteins disrupt membrane integrity, both in vitro and in vivo. The membrane interaction and subsequent aggregation has been briefly contrasted to aggregation of α-synuclein and IAPP in solution. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.

show abstract

Section: Structures In Solutionmentioning

confidence: 62%

Membranes as modulators of amyloid protein misfolding and target of toxicity

Rawat

Langen

Varkey

2018

Biochimica et Biophysica Acta (BBA) - Biomembranes

Self Cite

View full text Add to dashboard Cite

show abstract

“…IAPP is an amyloidogenic peptide that is co-secreted with serotonin from pancreatic beta cells, and its membrane interaction has been linked to Type II diabetes [43][44][45] . We have already shown that the oligomeric form of this peptide has a large membrane affinity, which may partly explain its biologically toxic role 42 . IAPP oligomers prefer to bind to the disordered phase of the lipid bilayer (unpublished), which in the light of the current results suggests that IAPP binding to the cell membrane may be modulated by serotonin.…”

Section: Serotonin Increases Membrane Binding Of Amyloid Oligomersmentioning

confidence: 98%

“…Furthermore, membrane protein function is strongly related to the elastic properties of the bilayer 41 . We probed the affinity of IAPP oligomers (synthesis of which is described previously 42 ) to the membrane of live cells in the presence of extracellular serotonin. IAPP is an amyloidogenic peptide that is co-secreted with serotonin from pancreatic beta cells, and its membrane interaction has been linked to Type II diabetes [43][44][45] .…”

Section: Serotonin Increases Membrane Binding Of Amyloid Oligomersmentioning

confidence: 99%

Receptor-independent membrane mediated pathways of serotonin action

Dey

Surendran

Enberg

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

AbstractSerotonin is a neurotransmitter as well as a somatic signaling molecule, and the serotonergic system is a major target for psychotropic drugs. Serotonin, together with a few related neurotransmitters, has recently been found to exhibit an unexpectedly high lipid membrane affinity1–3. It has been conjectured that extrasynaptic serotonin can diffuse in the lipid membrane to efficiently reach remote receptors (and receptors with buried ligand-binding sites)4, providing a mechanism for the diffuse ‘volume’ neurotransmission that serotonin is capable of5–10. Here we show that membrane binding by serotonin can directly modulate membrane properties and cellular function, independent of its receptor-mediated actions. Atomic force microscopy shows that serotonin binding makes artificial lipid bilayers softer. It induces nucleation of liquid disordered domains inside the raft-like liquid-ordered domains in a ternary bilayer displaying phase separation. Solid-state NMR spectroscopy corroborates this data, revealing a rather homogeneous decrease in the order parameter of the lipid chains in the presence of serotonin. In the RN46A immortalized serotonergic neuronal cell line, extracellular serotonin enhances transferrin receptor endocytosis, an action exerted even in the presence of both broad-spectrum serotonin receptor and transporter inhibitors. Similarly, it increases the binding and internalization of Islet Amyloid Polypeptide (IAPP) oligomers, suggesting a connection between serotonin, which is co-secreted with IAPP by pancreatic beta cells, and the cellular effects of IAPP. Our results uncover a hitherto unknown serotonin-bilayer interaction that can potentiate key cellular processes in a receptor-independent fashion. Therefore, some pathways of serotonergic action may escape potent pharmaceutical agents designed for serotonin transporters or receptors. Conversely, bio-orthogonal serotonin-mimetics may provide a new class of cell-membrane modulators.

show abstract

“…The structural characteristics of the IAPP oligomers have also been investigated by vibrational spectroscopy. Rawat and co-workers used both FTIR and Raman spectroscopy to investigate the conformation of the peptide chain in the different aggregation states of IAPP [58]. Both FTIR and Raman spectra of the IAPP oligomers suggest a predominantly α-helical conformation (together with significant β-sheet content) of the peptide chain in the oligomeric state, while in fibrils the peptide is predominantly in a β-sheet conformation.…”

Section: Backbone Vibrational Probementioning

confidence: 99%

Vibrational Approach to the Dynamics and Structure of Protein Amyloids

Lantz

2019

Molecules

View full text Add to dashboard Cite

Amyloid diseases, including neurodegenerative diseases such as Alzheimer’s and Parkinson’s, are linked to a poorly understood progression of protein misfolding and aggregation events that culminate in tissue-selective deposition and human pathology. Elucidation of the mechanistic details of protein aggregation and the structural features of the aggregates is critical for a comprehensive understanding of the mechanisms of protein oligomerization and fibrillization. Vibrational spectroscopies, such as Fourier transform infrared (FTIR) and Raman, are powerful tools that are sensitive to the secondary structure of proteins and have been widely used to investigate protein misfolding and aggregation. We address the application of the vibrational approaches in recent studies of conformational dynamics and structural characteristics of protein oligomers and amyloid fibrils. In particular, introduction of isotope labelled carbonyl into a peptide backbone, and incorporation of the extrinsic unnatural amino acids with vibrational moieties on the side chain, have greatly expanded the ability of vibrational spectroscopy to obtain site-specific structural and dynamic information. The applications of these methods in recent studies of protein aggregation are also reviewed.

show abstract

Aggregation-induced conformation changes dictate islet amyloid polypeptide (IAPP) membrane affinity

Cited by 23 publications

References 53 publications

Membranes as modulators of amyloid protein misfolding and target of toxicity

Membranes as modulators of amyloid protein misfolding and target of toxicity

Receptor-independent membrane mediated pathways of serotonin action

Vibrational Approach to the Dynamics and Structure of Protein Amyloids

Contact Info

Product

Resources

About