Enzymatic and non-enzymatic functions of the lysyl oxidase family in bone

Abstract

Advances in the understanding of the biological roles of the lysyl oxidase family of enzyme proteins in bone structure and function are reviewed. This family of proteins is well-known as catalyzing the final reaction required for cross-linking of collagens and elastin. Novel emerging roles for these proteins in the phenotypic development of progenitor cells and in angiogenesis are highlighted and which point to enzymatic and non-enzymatic roles for this family in bone development and homeostasis and in disease. The explosion of interest in the lysyl oxidase family in the cancer field highlights the need to have a better understanding of the functions of this protein family in normal and abnormal connective tissue homeostasis at fundamental molecular and cellular levels including in mineralized tissues.

Keywords: Angiogenesis; Bone; Cell differentiation; Cell proliferation; Collagen; Lysyl oxidase; Progenitor cell.

Figure 1. Major biosynthetic collagen and elastin cross-links

Red residues indicate the lysine or hydroxylysine residues not modified by lysyl oxidases. Dehydroaldohistidine can react further with an unmodified hydroxylysine residue to form an aldimine resulting in the tetravalent cross-link dehydrohydroxymerodesmsine (not shown).

Figure 2. Domain structures of lysyl oxidase family members

Signal peptide, propeptide and enzyme domains are shown schematically with numbers of amino acids per domain indicated for human family members. The enzyme domains (red) contain copper binding sequences and the LTQ cofactor produced after translation. The lysyl oxidase family can be thought of as having two subfamilies consisting of LOX and LOXL1 as one subfamily, and LOXL2 – LOXL4 as the second, based on the degrees of sequence identity, particularly in the propeptide regions.

Figure 3. The structure of the LTQ cofactor

This structure is generated by posttranslational modification in the enzyme domain of all lysyl oxidase isoforms, determined by analogy with rat and bovine LOX [49]. The amino acid numbering shown are the relevant human LOX lysine and tyrosine residues.

Figure 4. Conserved copper-binding cysteine and histidine-rich region (yellow) and LTQ lysine and tyrosine residues (blue)

These amino acid sequences contain key features of lysyl oxidase family enzyme active sites. Numbers to the right indicate residue numbers shown for human LOX.