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

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

JID Innov. 2022 Mar 9;2(3):100114. doi: 10.1016/j.xjidi.2022.100114. eCollection 2022 May.

Authors

Affiliations

¹ Department of Clinical Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
² Department of Dermatology, Faculty of Medicine, Oita University, Yufu, Oita, Japan.
³ Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan.
⁴ Department of Biochemistry II, Faculty of Medicine, Oita University, Yufu, Oita, Japan.

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.

Keywords: CD, circular dichroism; K5, keratin 5; K5/14, keratin 5/14; PLCA, primary localized cutaneous amyloidosis.