Identification of glutamine and lysine residues in Alzheimer amyloid βA4 peptide responsible for transglutaminase‐catalysed homopolymerization and cross‐linking to α₂M receptor

Abstract

Theb-amyloid peptide @A4), derived from a larger amyloid precursor protein, is the principal component of senile plaques in Alzheimer's disease. Here we report that the full-length (l-40) synthetic /3A4 peptide, containing one glutamine and two lysine residues, is able to form homopolymers in a transglutaminase-mediated reaction. Moreover, transglutaminase catalysed the formation of heteropolymers in reactions of /?A4 with a,M receptor, a constituent of amyloid plaques, and with extracellular matrix proteins. Incorporation of site-specific probes followed by enzymatic digestion and sequencing of tracer-containing fractions demonstrated that both Lys I6 Lys2* and Gin" in /?A4 were susceptible to cross-linking by , transglutaminase.

Removal of lactoferrin from plasma is mediated by binding to low density lipoprotein receptor‐related protein/α2‐macroglobulin receptor and transport to endosomes

“…This process elevates plasma Lf concentrations tenfold and even more at the site of the acute response. Other ligands of LRP/ct2MR like ~2M, PA/PAI-land apoE are also involved in these metabolic situations [36][37][38][39][40] pointing towards a concerted action of their receptor in this condition. As an iron complexing glycoprotein, Lf might sequester free iron in the extracellular space delivering it via LRP/c~2MR mediated endocytosis into hepatocytes and other cells expressing LRP/~2MR, like macrophages.…”

Propagating structure of Alzheimer’s β-amyloid (10–35) is parallel β-sheet with residues in exact register

“…The decision of where to place these labels was aided by studies of tissue transglutaminase (tTg) crosslinking of A␤ (66)(67)(68)(69)(70). This enzyme specifically crosslinks Gln 15 and Lys 16 of A␤ but never involves Lys 28 (70), suggesting that Gln 15 and Lys 16 are proximate in an aggregated form of A␤.…”

Substrate Requirements for Transglutaminases

“…Fourteen identified substrate lysines for TGC (26 -32) have recently been tabulated (17). Another lysine substrate for TGC has since been identified in Alzheimer amyloid protein ␤A4, located in the sequence -SNKG- (33). For factor XIII the substrate lysine in the fibrin ␥ chain has been characterized long ago (-GAKQ-) (34).…”