HSP47: History

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 19^th 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 20^th 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.