Our overall goal is to understand biological functions and pathologies in structural terms, by focusing on proteins and macromolecular complexes, using X-ray crystallography as the major experimental tool.
Part of our work is centered on the family of proteins characterized by the presence in its members of the amino acid kinase (AAK) fold described by us. This family includes important catalysts/controllers of metabolic pathways, some of them centrally involved in inborn pathologies. We aim at deciphering the function, regulation and evolutionary interrelations of AAK family members by characterizing structures of these members, and to rationalize and predict the effects of the clinical mutations affecting those members that are the targets of inborn errors. Our study also deals with polyfunctional proteins and supramolecular complexes involving AAK family members, including a complex with the PII signaling protein.
PII-PipX complex. PII(in solid surface representation) sequesters PipX (in ribbon representation). When ammonia is scarce 2-oxoglutarate levels increase and this ligand binds to PII, triggering the retraction of the T-loops (vertical legs of PII), releasing PipX, which is left free to activate the NtcA transcription factor.
Actually, the structural deciphering of PII signaling is another of our key goals. PII is a very ancient, conserved, and widespread signaling protein (although not found in animals) that transduces carbon/energy/nitrogen abundance signals. It interacts with protein targets, including channels, enzymes and gene regulators, and it is controlled allosterically and by covalent modification. Thus, PII is the center of a wide regulatory universe that includes control of PII by a complex machinery, and control by PII of many key processes like membrane passage, metabolic pathways, transcription regulation and even signaling by other proteins. We believe that the detailed structural knowledge of this regulatory network is essential, since, in addition to its intrinsic interest, it might provide key clues for manipulating many important processes of biotechnological and even ecological and public health interest.
Another chunk of our work deals with the catalysts of the urea cycle and of arginine biosynthesis and utilization. These proteins, frequently quite complex and not well understood, include potential bacterial targets as well as human catalysts that when defective or inhibited/inactivated by external or internally produced agents, cause hyperammonemia (a devastating condition that if not treated aggressively can lead to death). We aim at structural and functional understanding of these catalysts, to characterize targets, rationalize effects, predict outcomes and even to propose treatments.
Our work is under the institutional auspices of the Spanish Research Council (CSIC), and the Center for Networked Biomedical Research on Rare Diseases (CIBERER, Instituto de Salud Carlos III), of which we are group 739. The IP belongs to the Prometeo programme for excellence groups of the Valencian Government