Lepidosaur ß-keratin chains with four 34-residue repeats: Modelling reveals a potential filament-crosslinking role

• Published in: Journal of structural biology 2020-01, Vol.209 (1), p.107413-107413, Article 107413
• Main Authors: Fraser, R.D. Bruce, Parry, David A.D.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence - genetics; Animals; Conserved Sequence; Cytoskeleton - genetics; Cytoskeleton - ultrastructure; Epidermis - chemistry; Epidermis - ultrastructure; Humans; Inter-filamentous crosslinks; Intermediate Filaments - genetics; Intermediate Filaments - ultrastructure; Keratins - chemistry; Keratins - genetics; Keratins - ultrastructure; Lizards - genetics; Microscopy, Electron; Protein Conformation; Protein Conformation, beta-Strand; Reptiles - genetics; Sequence comparisons; β-keratin; β-sandwich
• ISSN: 1047-8477; 1095-8657
• DOI: 10.1016/j.jsb.2019.107413

•The four 34-residue repeat chains may have repeats in different filaments thereby crosslinking them together.•This would endow the epidermal appendage with lateral integrity and structural reinforcement.•This is the first suggestion of a potential crosslinker in lepidosaur ß-keratin filaments. ß-keratin chains contain a characteristic and homologous 34-residue sequence, which is believed to adopt a twisted ß-sheet conformation that assembles in an antiparallel manner with a similar sheet in a second chain to form a ß-sandwich. These sandwiches are, in turn, related to one another by a left-handed four-fold screw axis to generate a helical structure that forms the core of the 3.4 nm diameter filaments observed by electron microscopy and deduced from X-ray fibre diffraction. Recently, it has been shown that one ß-keratin chain, with a molecular weight approximately twice that of the majority of ß-keratin chains, is conserved across the lepidosaurs (lizards, snakes and tuatara). Uniquely, it contains four 34-residue repeats. Although this chain is a minor component the observation that the entire chain shows a high degree of sequence conservation between species suggests an important structural/functional role in vivo. Modelling shows that only six families of structures are physically possible. In three of these the repeats exist within a single filament and might therefore act in a filament nucleation role. In the second three families the repeats exist in two, three or four filaments, implying that their function may be to act as an inter-filament crosslinker, thereby providing lateral reinforcement to the epidermal appendage. The favoured model is one in which the first two repeats form a β-sandwich in one filament and the second two repeats form a β-sandwich in a neighbouring filament. Links between alternating up- and down-pointing β-sheets would provide optimum connectivity.