Fibulin-4 Accelerates Amyloid Formation by Binding with a Keratin 5 Peptide Fragment

Fumihiko Katagiri,Daisuke Ueo,Yumi Okubo-Gunge,Aya Usui,Sayaka Kuwatsuka,Yoshiko Mine,Keisuke Hamada,Sakuhei Fujiwara,Takako Sasaki,Motoyoshi Nomizu,Atsushi Utani

doi:10.1016/j.xjidi.2022.100114

Abstract

Keratins are the major amyloid fibril component in localized cutaneous amyloidosis. We analyzed the amyloid components in the skin of patients with localized cutaneous amyloidosis by immunohistochemical staining using antisera against extracellular matrix proteins and keratin 5 (K5). Fibulin-4 and K5 colocalized in the amyloid deposits. Using 14 synthetic peptides, we screened for amyloidogenic sequences in the C-terminal region of K5, including the α-helical rod domain and the tail domain. Two peptides stained with thioflavin T possessed a β-sheet structure and formed amyloid-like fibrils. Among the amyloidogenic peptides, a peptide KT5-6 (YQELMNTKLALDVEIATYRKLLEGE) derived from the α-helical rod domain of K5 specifically bound to fibulin-4. In addition, amyloid formation of KT5-6 was accelerated by fibulin-4. These results suggest that degraded fragments of K5 containing the KT5-6 sequence form amyloid fibrils with fibulin-4. The data further suggest that degraded fragments of K5 and fibulin-4 have the potential to initiate cutaneous amyloidosis.

Highlights

Amyloidosis is caused by abnormal extracellular matrix deposition and accumulation of insoluble fibrous proteins that have a b-sheet structure
We describe the colocalization of keratin 5 (K5) and fibulin-4 in cutaneous amyloid deposits by immunohistochemical staining
We localized an active site on K5 for amyloid formation using synthetic peptides that were screened for amyloid-like fibril formation and fibulin-4 binding

Summary

Introduction

Amyloidosis is caused by abnormal extracellular matrix deposition and accumulation of insoluble fibrous proteins that have a b-sheet structure. Amyloidosis can result in the dysfunction of either the whole body or specific organs (Glenner, 1980). Localized cutaneous amyloidosis has been divided into primary localized cutaneous amyloidosis (PLCA) and secondary localized cutaneous amyloidosis (Wong, 1987). Both types of localized cutaneous amyloidosis are associated with the deposition of amyloid only in the skin, without the involvement of internal organs. Lichen amyloidosis is the most common form of PLCA and ordinarily presents as relentless pruritic plaques on the extensor surfaces of the lower legs and on the forearms and back (Bolognia et al, 2008; Wang, 1990; Westermark et al, 1999). Secondary localized cutaneous amyloidosis is observed in skin tumors, including basal cell carcinomas, Bowen’s carcinoma, and benign skin tumors (Breathnach, 1988; Breathnach and Hintner, 1990)

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