Residue-based propensity of aggregation in the Tau amyloidogenic hexapeptides AcPHF6* and AcPHF6

Abha Dangi; Abhishek Ankur Balmik; Archana Kisan Ghorpade; Nalini Vijay Gorantla; Shweta Kishor Sonawane; Subashchandrabose Chinnathambi; Udaya Kiran Marelli

doi:10.1039/d0ra03809a

Residue-based propensity of aggregation in the Tau amyloidogenic hexapeptides AcPHF6* and AcPHF6

RSC Adv. 2020 Jul 21;10(46):27331-27335. doi: 10.1039/d0ra03809a.

Authors

Abha Dangi^{1

2

3}, Abhishek Ankur Balmik^{3

4}, Archana Kisan Ghorpade^{1

2}, Nalini Vijay Gorantla^{3

4}, Shweta Kishor Sonawane^{3

4}, Subashchandrabose Chinnathambi^{3

4}, Udaya Kiran Marelli^{1

2

3}

Affiliations

¹ Central NMR Facility, CSIR-National Chemical Laboratory Dr HomiBhabha Road 411008 Pune India.
² Division of Organic Chemistry, CSIR-National Chemical Laboratory Dr HomiBhabha Road 411008 Pune India.
³ Academy of Scientific and Innovative Research (AcSIR) 110025 New Delhi India.
⁴ Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory Dr HomiBhabha Road 411008 Pune India.

Abstract

In Alzheimer's disease and related tauopathies, the aggregation of microtubule-associated protein, Tau, into fibrils occurs via the interaction of two hexapeptide motifs PHF* ²⁷⁵VQIINK²⁸⁰ and PHF ³⁰⁶VQIVYK³¹¹ as β-sheets. To understand the role of the constituent amino acids of PHF and PHF* in the aggregation, a set of 12 alanine mutant peptides was synthesized by replacing each amino acid in PHF and PHF* with alanine and they were characterized by nuclear magnetic resonance (NMR) spectroscopy, circular dichroism (CD), transmission electron microscopy (TEM) and ThS/ANS fluorescence assay. Our studies show that while the aggregation was suppressed in most of the alanine mutant peptides, replacement of glutamine by alanine in both PHF and PHF* enhanced the fibrillization.