Crystal structure of a Serpin A1 trimer. The diagram features three copies of Serpin A1 in assembly
Hsp47 is an ER-resident procollagen-specific molecular chaperone belonging to clade H of the SERPIN superfamily of serine proteinase inhibitors. Although proteinase inhibitory functioning has already been described in the late 19th century by Claudio Fermi and Leone Pernossi, the isolation of the first serpins antithrombin and α1-antitrypsin occurred only half a century later 16. In 1980, Hunt and Dayhoff identified ovalbumin, antithrombin-III, and α1-proteinase inhibitor (α1-PI) as being part of a new superfamily which they termed “serpins” (serine protease inhibitors) 17. It is interesting to note that this new family not only comprises enzymatic inhibitors such as α1-PI but also non-inhibitory molecules such as ovalbumin. During the same period, the first crystal structures of serpins were elucidated 18, 19. Meanwhile, several thousand serpins have been characterized and systematically categorized 20. Serpins now comprise the most common proteinase inhibitors and can be found in all five kingdoms of life 20. Hsp47 was originally characterized as a 47 kDa collagen-binding protein in chicken embryos whose expression is up-regulated upon heat shock 15. Independent investigations identified Hsp47 in mice as colligin 10 and in rats as gp46 21 as well. The intracellular location of Hsp47 to the ER has been verified by Saga et al. within the same decade 22. Recently, the group of Kouki Kitagawa identified the Hsp47-binding structural epitope in the procollagen triple helix and also the Hsp47-binding motif in the primary structure 23. More recently, the first crystal structures of Hsp47 from canine, either in its free form and in complex with different synthetic collagen model peptides, were determined by Widmer and colleagues 24. Using chicken Hsp47 as a model, Yagi-Utsumi and co-workers performed the first structural study on Hsp47-procollagen interaction by means of NMR and mutational analysis leading to the identification of the procollagen-binding site within the B/C β-barrel domain of Hsp47 25. The pH-sensitive nature of procollagen to Hsp47 binding was proposed for the first time at the end of the 20th century by in vitro binding and inhibitor assays, respectively 22,26. Several important residues crucially involved in Hsp47-procollagen interaction have recently been identified with His274 as being the key residue for pH-dependent procollagen release 27. In the course of the last years, several diseases have been linked to Hsp47 and its interaction partners, such as collagen-related and neurodegenerative diseases as well as cancer.