Biochemistry and Molecular Genetics
Phone: (212) 570-3388
Email: chuang@nybloodcenter.org

We, in the Laboratory of Biochemistry and Molecular Genetics, have a keen interest in understanding the structure-function relationship as well as the regulatory mechanism of proteins and their macromolecular assemblies in eukaryotic organisms.  We are also interested in the evolutionary history of proteins in the context of speciation that highlights their functional conservation and diversification.  At present we are working on three projects, each characterizing a class of proteins, and are employing them as experimental model systems to address important biological and physiological questions to illuminate the fundamental principles that govern the working of these macromolecular machineries.  We utilize biochemical, cell, genetic, and molecular biological approaches in our investigations and foster collaboration inside and outside of our institution.

Project 1: The Rh/Mep/Amt Superfamily of Multi-passing Membranous Proteins. The Rh/Mep/Amt superfamily of proteins, found in all domains of life, is an important and unique class of membrane proteins implicated in transport of carbon dioxide (CO₂) and ammonia (NH₃/NH₄⁺).  This laboratory has extended the seminal discovery in red cells of the Rh (Rhesus) blood group antigen as the cause of fetal hemolytic disease and pioneered research of Rh genetic polymorphism and Rh antigen-related homologs in non-erythroid tissues and various nonhuman species.  For this project, multiple approaches are being taken to investigate these proteins at the molecular, cellular, and organism levels, including targeted gene elimination and gene-specific suppression in low organisms.  Our ultimate goal is to determine the molecular basis for their physiological function and developmental role, linking these vital cellular activities to the homeostasis of systemic pH regulation.

Project 2:  Signaling Ser/Tyr Protein Kinases and Their Scaffolding Organization. Protein kinases including serine and tyrosine kinase classes are fundamental hubs that connect to cellular networks and pathway activities, and this global function has greatly been expanded during metazoan evolution. These cellular regulators, while promoting the phosphorylation of their substrate proteins, are in themselves subject to regulation, such as scaffolding organization, and are frequent targets of oncogenic transformation. This lab has first cloned a new protein kinase named Dusty, which is conserved in metazoans in the primitive Placozoan T. adhaerens to our species, while secondarily lost in worm and insects. The Dusty protein kinase is unique in that its N-terminal domain shares no sequence homology with any known proteins but has highly conserved SH-containing cysteine residues that implicate a role in oxidoreduction. Moreover, Dusty protein kinase is a frequent target of tumorigenesis, whose broad and multi-tissue expression is down-regulated or abolished in many types of cancers, suggesting a tumor suppressor function. In this project, our goal is to identify the substrate proteins of Dusty protein kinase and decipher its functional link to other signaling pathways in oncogenic progression.      

Project   3: The STIP Family of Proteins and the Cellular Body Stiposome. The cell nucleus, a hallmark organelle and compartment of eukaryotes, serves to store the genome blueprint, secure its stability, and separate gene transcription from protein translation. Architecturally, it lacks an elaborate endomembrane system and cytoskeletal meshwork but contains many dynamic subnuclear structures or macromolecular assemblies together named as nuclear bodies, which function to coordinate intranuclear genomic activities. We have characterized the STIP protein family as a unique class of multidomain proteins ubiquitously expressed in metazoans that are capable of forming a new type of nuclear bodies dubbed stiposomes (STIP-NB).  We have demonstrated that stip is essential for embryogenesis and viability of the worm C. elegans and the gene suppression-led lethal phenotype could be rescued with a stip gene from fly or human.  In this project we set out to identify the variety of cellular molecular signals that govern protein-protein interactions in the dynamic assembly and organization of STIP-NB.  Our long-term goal is to determine the precise function and regulatory mechanism of STIP-NB and link its compositional dynamics to its multi-functional role in orchestrating nuclear processing activities.