Crystal Structure of a Novel Regulatory 40-kDa Mammary Gland Protein (MGP-40) Secreted during Involution

Abstract

We have determined the crystal structure of a novel regulatory protein (MGP-40) from the mammary gland. This protein is implicated as a protective signaling factor that determines which cells are to survive the drastic tissue remodeling that occurs during involution. It has been indicated that certain cancers could surreptitiously utilize the proposed normal protective signaling by proteins of this family to extend their own survival and thereby allow them to invade the organ and metastasize. In view of this, MGP-40 could form an important target for rational structure-based drug design against breast cancer. It is a single chain, glycosylated protein with a molecular mass of 40 kDa. It was isolated from goat dry secretions and has been cloned and sequenced. It was crystallized by microdialysis from 20 mg ml Mammary glands secrete a class of very important proteins during involution. We have isolated a glycoprotein from goat dry secretions which has a molecular mass of 40 kDa. This mammary gland protein has been named MGP-40.

High serum YKL-40 level in patients with small cell lung cancer is related to early death

“…The crystallographic three-dimensional structure of human [10,11] and goat YKL-40 [12] are described but the site and mode of binding to cell surface receptors is not yet known. YKL-40 is a heparin and chitin-binding lectin [3,13] without chitinase activity [1,13].…”

Family 18 chitolectins: Comparison of MGP40 and HUMGP39

“…Recently, an x-ray structure for one member of the chitolectin class of proteins MGP40 (PDB ID: 1LJY) was determined [5]. The structure is consistent with the (β/α) 8 barrel topology of the Family 18 glycosidase proteins .…”

“…1). We found that since Arg84 is conserved between the two proteins, it is not the cause for the lack of oligosaccharide binding in MGP40 as proposed by Mohanty et al [5]. Hence we compared the aromatic residues in both proteins, focusing on the Trp and Tyr residues present in the floor of the binding groove that are likely to interact strongly with the sugar molecules.…”

“…To further investigate the +1 binding site, we superimposed structures from different Family 18 proteins. We observe that the proteins with no sugar bound, MGP40 and two HumGP39 structures (pdb ids: 1LJY, 1NWR, 1HJX) [5,9,27] have the Trp in a different "pinching" orientation as opposed to the "stacking" orientation in structures with the sugar bound (Fig. 4).…”

“…The proteins belonging to the enzymatically inactive class are referred to as, chitolectins and have a binding site that is highly similar to the catalytic Family 18 enzymes. We present a comparison of the recently obtained structures of two Family 18 chitolectins, MGP40 (Mohanty, Singh et al, 2003) and HumGP39 (Fusetti, Pijning et al, 2003;Houston, Anneliese et al, 2003) with glycosidases active site. We compare the sequence and the structure of these two Family 18 proteins.…”