Microfibril-associated glycoproteins MAGP-1 and MAGP-2 in disease

Abstract

Microfibril-associated glycoproteins 1 and 2 (MAGP-1, MAGP-2) are protein components of extracellular matrix microfibrils. These proteins interact with fibrillin, the core component of microfibrils, and impart unique biological properties that influence microfibril function in vertebrates. MAGPs bind active forms of TGFβ and BMPs and are capable of modulating Notch signaling. Mutations in MAGP-1 or MAGP-2 have been linked to thoracic aneurysms and metabolic disease in humans. MAGP-2 has also been shown to be an important biomarker in several human cancers. Mice lacking MAGP-1 or MAGP-2 have defects in multiple organ systems, which reflects the widespread distribution of microfibrils in vertebrate tissues. This review summarizes our current understanding of the function of the MAGPs and their relationship to human disease.

Keywords: Aneurysms; Bone; Cancer; Fibrillin; MAGP; Microfibril; Microfibril-associated glycoprotein; Obesity.

Figure 1

Top) Functional domain diagram of MAGP-1 and sequence comparison of MAGP-1 and MAGP-2. The highly acidic growth factor binding domain of MAGP-1 (red underline) near the amino terminus is the site for TGFβ interaction. The adjacent glutamine-rich motif (blue underline) mediates self-interaction between MAGP-1 monomers through the formation of an extremely stable parallel β-pleated “tape” structure. Cysteine residues are contained in the C-terminal half of both proteins where seven cysteine residues contribute to the conserved matrix binding domain (shaded region). The last five cysteines in MAGP-1 suggest a ShK motif at the C-terminal end of the protein (green underline, MAGP-1). The arrowhead indicates a furin cleavage site in MAGP-2 that is absent in MAGP-1. While there is relatively high sequence homology within the matrix binding domain of MAGP-1 and MAGP-2, sequences outside of this region share little homology. Other than the matrix binding domain, functional sequences in MAGP-2 have not yet been characterized. Bottom: MAGP and fibrillin gene expression in developing mouse aorta as determined by gene array analysis. Expression values in arbitrary units are plotted against developmental age, which begins at embryonic day 14 (E14) through 6 months (P6M). Expression of MAGP-1 is highest in the fetal and neonatal period and lowest in the adult. MAGP-2 shows the opposite expression pattern, being lowest in the fetal period and rising throughout the neonatal period to highest levels in adult tissue. Interestingly, fibrillin-1 has an expression pattern similar to MAGP-2 whereas fibrillin-2 follows the pattern of MAGP-1. It should be noted, however, that expression of both MAGPs is relatively high compared to other proteins at all stages of development.

Figure 2

Possible mechanisms for TGF growth factor regulation by MAGP. Top) MAGP blocks binding of the TGFβ-LLC to the microfibril by competing for a common interaction site on fibrillin. Bottom) MAGP serves to subdue TGFβ signaling by binding active growth factor after its release from the LLC. See text for details