Bioinformatic Analysis of Pathogenic Missense Mutations of Activin Receptor Like Kinase 1 Ectodomain

Abstract

Activin A receptor, type II-like kinase 1 (also called ALK1), is a serine-threonine kinase predominantly expressed on endothelial cells surface. Mutations in its ACVRL1 encoding gene (12q11-14) cause type 2 Hereditary Haemorrhagic Telangiectasia (HHT2), an autosomal dominant multisystem vascular dysplasia. The study of the structural effects of mutations is crucial to understand their pathogenic mechanism. However, while an X-ray structure of ALK1 intracellular domain has recently become available (PDB ID: 3MY0), structure determination of ALK1 ectodomain (ALK1EC) has been elusive so far. We here describe the building of a homology model for ALK1EC, followed by an extensive bioinformatic analysis, based on a set of 38 methods, of the effect of missense mutations at the sequence and structural level. ALK1EC potential interaction mode with its ligand BMP9 was then predicted combining modelling and docking data. The calculated model of the ALK1EC allowed mapping and a preliminary characterization of HHT2 associated mutations. Major structural changes and loss of stability of the protein were predicted for several mutations, while others were found to interfere mainly with binding to BMP9 or other interactors, like Endoglin (CD105), whose encoding ENG gene (9q34) mutations are known to cause type 1 HHT. This study gives a preliminary insight into the potential structure of ALK1EC and into the structural effects of HHT2 associated mutations, which can be useful to predict the potential effect of each single mutation, to devise new biological experiments and to interpret the biological significance of new mutations, private mutations, or non-synonymous polymorphisms.

Specificity and Structure of a High Affinity Activin Receptor-like Kinase 1 (ALK1) Signaling Complex

“…7A). Consistent with previous predictions, mutations that map to the highly conserved cysteine residues disrupt the core intramolecular disulfide bonds (33,34). We found that only three mutations (H66P, G79R, and H87D) directly affect residues at the BMP9 interface.…”

Anti-human Activin Receptor-like Kinase 1 (ALK1) Antibody Attenuates Bone Morphogenetic Protein 9 (BMP9)-induced ALK1 Signaling and Interferes with Endothelial Cell Sprouting

“…In a model of the ALK1, the structure of this region was predicted to contain several residues involved in the ALK1/ BMP9 interaction (35).…”

Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes

“…Both patients carry ACVRL1 mutations in exon 3, an in-frame deletion (p. l55_V56del), and a missense mutation (p. C51Y). The missense mutation was included in the paper by Scotti et al 28 and was among the mutations with the higher destabilizing effects on protein structure. The presence of hepatic AVMs fits with its increased frequency in females carrying ACVRL1 mutations; 13 both cases are younger than those more severely affected, and, currently, younger age is likely a better explanation for their mild GI presentation of the disease than the presence of a peculiar mutation.…”