Mohammadi Lab's Research Interest
Dr. Moosa Mohammadi, Ph.D., is the leading authority in the structural biology of fibroblast growth factor (FGF) signal transduction system. His research group at the Department of Biochemistry and Molecular Biology in the New York University School of Medicine employs x-ray crystallography and other contemporary biophysical techniques to explore the molecular mechanisms of FGF signaling in human development, metabolism and disease. A major part of Prof. Mohammadi’s research is devoted to elucidating the mechanism of action of numerous gain-of-function mutations in FGF receptors (FGFR) that lead to human craniosynostosis and dwarfism syndromes.
Dr. Moosa Mohammadi, Ph.D.
Dr. Mohammadi received his Ph.D. in Biochemistry from the University of Zurich in Switzerland and completed his postdoctoral training in the laboratory of Dr. Joseph Schlessinger in the Department of Pharmacology at New York University School of Medicine. In 1997, he established his independent research group in the same department (now department of Biochemistry & Molecular Pharmacology) where he is currently a tenured Professor. Dr. Mohammadi has been studying the mechanisms of FGF signaling for nearly two decades. Using X-ray crystallography complemented with contemporary biophysical and biochemical methods including Surface Plasmon Resonance spectroscopy (SPR), Isothermal Titration Calorimetry (ITC), mass spectrometry, in vitro kinase assay, and cell-based assay his lab has made major contributions to our current understanding of the molecular mechanisms of FGF signaling in human development, metabolism and disease. His deep knowledge of structure-function relationship of FGFs and FGFRs has allowed him to engage in numerous fruitful collaborations with developmental biologists, endocrinologists, clinicians, and cell and cancer biologists in the FGF field to tackle key biological problems in FGF signaling.
Gain-of-function mutations in FGFR1, FGFR2 and FGFR3 are responsible for many forms of craniosynostosis and dwarfism syndromes. With significance to the mission of the Growing Stronger Organization, Dr. Mohammadi’s lab has elucidated the structural basis by which these pathogenic mutations lead to over-activation of FGFRs in these skeletal diseases. His structural and biochemical analysis of pathogenic gain-of-function mutations in the tyrosine kinase domain of FGFR have led to the discovery of a novel autoinhibitory “molecular brake” at the kinase hinge/interlobe region that is disengaged to different extent by different mutations, leading to a range of ligand-independent activation of FGFR. Likewise his structural and biochemical investigations of ligand-dependent FGFR2c p.S252W and FGFR2c p.P253R mutations, responsible for Apert syndrome (AS), have revealed that these mutations introduce additional contacts between the mutated FGFR and FGF to increase the affinity of the mutated FGFR for both its cognate FGFs and for FGFs that are outside the normal specificity profile of wild type FGFR. These studies underscore the power of applying structural biology to understanding the molecular mechanism of human disease. Continued investigation of the structural biology of these pathogenic mutations should provide frameworks for rational design of small molecule inhibitors to tame these diseased FGFRs and hence find therapies for these human diseases.
Recent Research Progress on Skeletal Disorders
Mutations affecting Lys-650 of FGFR3 give rise to dwarfism syndromes of varying clinical severity. Five different substitutions of this hotspot codon, located on the A-loop, have been reported: K650T, K650N, K650Q, K650M, and K650E. Thanatophoric dysplasia type II (TDII) is a neonatal lethal syndrome and results exclusively from the K650E mutation. Substitution of Lys-650 with Met causes Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans (SADDAN) syndrome. In contrast, the K650N and K650Q mutations are associated with milder hypochondroplasia (HCH). The K650T mutation also leads to a milder HCH but the affected patients additionally suffer from acanthosis nigricans. Our in vitro kinase assay data show that these five pathogenic mutations have different capacities to elevate the intrinsic kinase activity of FGFR3 kinase in the following order K659E>K659M>K659N>K659Q>K659T. Hence our results reveal a correlation between the degree of kinase activation imparted by these mutations and the severity of the skeletal malformations they cause. We are now in the midst of refining the crystal structures of these five pathogenic FGFR3 kinases. These structures will allow us to delineate the molecular basis by which these mutations impart different degree of kinase activation and hence explain the observed clinico-functional correlation for these pathogenic mutations.