My laboratory’s research focus is biophysics and the structural biology of proteins that regulate signal transduction processes at the membrane surface. Dysregulation of these proteins is implicated in various human pathologies such as cancer, cardiac disease, Alzheimer’s, and diabetes. We use a combination of biophysical and biochemical techniques to investigate the structure, dynamics, and membrane interactions of these protein systems. The objective is to understand the mechanism of their action at the membrane and how this information can be used to design better therapeutic agents.

Protein kinase C: regulation and tumor-promoting response

Protein Kinases C (PKC) defines a family of lipid-activated kinases that play vital roles in the phosphoinositide-signaling pathway. Classical views as to how the paradigm-shifting discovery recently overturned PKCs function, that PKC – long considered to function exclusively as a tumor promoter – phenotypes as a tumor suppressor in 8% of mutations associated with human cancers. Those surprising discoveries underscore the key challenges in the field – a need for the availability of both activators and inhibitors of PKC function, and the ability to target the protein in an isoform-specific manner. Addressing these challenges demands an atomic-level understanding of how lipids and tumor-promoting agents regulate PKC activity. We use NMR spectroscopy, X-ray crystallography, fluorescence spectroscopy, and biochemical techniques to gain insight into PKC regulation’s structural basis.

Y. Yang, C. Shu, P. Li, T. I. Igumenova, Structural basis of protein kinase Ca regulation by the C-terminal tail. Biophys. J. 114, 1590–1603 (2018).

Xenobiotic metals ions: friends or foes?

The focus of this research direction is to understand the molecular mechanisms of signal transduction at the membrane surface through exploiting the unique physicochemical properties of xenobiotic metal ions. “Xenobiotic” is defined as a “chemical … that is foreign to a living organism”. Metal ions that do not have a nutritive value belong to this category; some examples include rare earth metals and potent environmental toxins, such as Cd, Pb, As, and Hg. We discovered that some xenobiotic metal ions, such as Pb2+ and the lanthanide series, Ln3+, have unique physicochemical properties to their interactions with oxygen-rich Ca2+-binding sites of C2 domains, a class of Ca2+-dependent peripheral membrane modules found in >100 signaling proteins. We are exploiting these unique properties to address long-standing mechanistic questions about signal transduction and membrane fusion mediated by PKC and Synaptotagmin 1.

S. Katti, S. B. Nyenhuis, B. Her, D. S. Cafiso, T. I. Igumenova, Partial metal ion saturation of C2 domains primes Synaptotagmin 1-membrane interactions. Biophys. J. 118, 1409–1423 (2020).

Lipid-binding protein modules and mechanisms of coincidence detection

Signaling proteins have a modular architecture that enables them to combine multiple lipid-sensing functions on the same polypeptide chain. We investigate the biophysical properties of the lipid-sensing protein domains and how their interplay modulates their structural properties and response to signaling lipids and metal ions.

M. D. Stewart and T. I. Igumenova, Toggling of diacylglycerol affinity correlates with conformational plasticity in C1 domains. Biochemistry 56, 2637–2640 (2017).

Molecular dynamics simulations of protein-membrane systems

How do signaling proteins recognize and capture signaling lipids in the membrane? This question requires an expansion of the available repertoire of experimental methods to atomistic molecular dynamics simulations. This is a new research direction in our laboratory. The current focus is on the conserved homology 1 (C1) domains that sense diacylglycerol, an important signaling lipid and metabolic precursor.