Natalia Jura, PhD

Assistant Professor
Cardiovascular Research Institute
Department of Cellular and Molecular Pharmacology
+1 415 514-1133
Research Overview: 

Cells maintain homeostasis by precisely responding to external growth stimuli. Our lab is interested in understanding how cells detect these extracellular growth signals and transmit them across the plasma membrane. A central role in this process is played by receptor tyrosine kinases (RTKs) and the ligand-dependent transition of their kinase domains from the inactive to the active state. The activated kinase domains initiate a phosphorylation cascade that results in activation of downstream signaling pathways. We want to gain a molecular understanding how ligand binding to the extracellular domains of the receptor results in activation of the intracellular kinase domains, how the active receptor establishes its specificity for substrate phosphorylation, and how the multi-protein signaling complexes assemble at the sites of active receptors. Our research will focus on the family of the Epidermal Growth Factor Receptors: EGFR/HER1/ErbB1, ErbB2, ErbB3 and ErbB4, and the MET family of receptor tyrosine kinases. Both receptor families represent leading clinical targets and our long-term goal is to develop new therapeutic strategies for targeting these receptors in human diseases.

Because RTKs are membrane proteins, they are difficult to study in vitro and despite decades of research, the high-resolution structures of the full-length receptors that visualize the connection between the extracellular and intracellular domains are still missing. Our lab will take advantage from the recent technologies that provide a platform for reconstitution of the transmembrane proteins in the membrane environment of lipid nanodiscs and lipid bilayers. We will apply these systems to pursue crystallography of the full-length receptors and their complexes with downstream effectors. We will pair these efforts with biochemical analysis of the reconstituted receptor signaling complexes in vitro and the quantitative cell signaling studies at the single cell level using flow cytometry.

Another critical aspect of RTK signaling is precise temporal regulation of their activation, which involves both keeping their basal activity low and restricting signal duration upon ligand binding. We will apply cell-based high throughput screening assays for mapping these basal autoinhibitory interactions and identifying novel feedback regulators of the ErbB and MET receptors. We are also interested in understanding how receptor signaling is fine-tuned by the actin cytoskeleton and sites of cell adhesion. EGFR/ErbB1 directly binds actin and both ErbB receptors and MET were shown to interact with the integrins. The molecular basis for these interactions and their functional consequences for receptor signaling are unclear due to complexity stemming from analyzing these processes in cells. We will work on developing an in vitro system where interaction between actin polymers, adhesion molecules and the receptors reconstituted in the membranes can be studied directly. Such system will allow investigating the interplay between actin binding and polymerization, and receptor organization at the membrane, and will yield fundamental insight into the cross-talk between receptor tyrosine kinase signaling and actin-dependent processes, such as cell adhesion and motility.

Primary Thematic Area: 
Cancer Biology & Cell Signaling
Secondary Thematic Area: 
Vascular & Cardiac Biology
Research Summary: 
Molecular basis for Receptor Tyrosine Kinase signaling across the plasma membrane

Websites

Publications: 

Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization.

Nature communications

Agnew C, Ayaz P, Kashima R, Loving HS, Ghatpande P, Kung JE, Underbakke ES, Shan Y, Shaw DE, Hata A, Jura N

Mutant HER2 needs mutant HER3 to be an effective oncogene.

Cell Reports Medicine

Raphael Trenker, Devan Diwanji, Natalia Jura

Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant.

bioRxiv : the preprint server for biology

Thorne LG, Bouhaddou M, Reuschl AK, Zuliani-Alvarez L, Polacco B, Pelin A, Batra J, Whelan MVX, Ummadi M, Rojc A, Turner J, Obernier K, Braberg H, Soucheray M, Richards A, Chen KH, Harjai B, Memon D, Hosmillo M, Hiatt J, Jahun A, Goodfellow IG, Fabius JM, Shokat K, Jura N, Verba K, Noursadeghi M, Beltrao P, Swaney DL, Garcia-Sastre A, Jolly C, Towers GJ, Krogan NJ

CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes.

Research square

Verba K, Gupta M, Azumaya C, Moritz M, Pourmal S, Diallo A, Merz G, Jang G, Bouhaddou M, Fossati A, Brilot A, Diwanji D, Hernandez E, Herrera N, Kratochvil H, Lam V, Li F, Li Y, Nguyen H, Nowotny C, Owens T, Peters J, Rizo A, Schulze-Gahmen U, Smith A, Young I, Yu Z, Asarnow D, Billesbølle C, Campbell M, Chen J, Chen KH, Chio US, Dickinson M, Doan L, Jin M, Kim K, Li J, Li YL, Linossi E, Liu Y, Lo M, Lopez J, Lopez K, Mancino A, Iii FM, Paul M, Pawar K, Pelin A, Pospiech T, Puchades C, Remesh S, Safari M, Schaefer K, Sun M, Tabios M, Thwin A, Titus E, Trenker R, Tse E, Tsui TKM, Feng F, Zhang K, Zhang Y, Zhao J, Zhou F, Zhou Y, Zuliani-Alvarez L, Agard D, Cheng Y, Fraser J, Jura N, Kortemme T, Manglik A, Southworth D, Stroud R, Swaney D, Krogan N, Frost A, Rosenberg O

CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes.

bioRxiv : the preprint server for biology

Gupta M, Azumaya CM, Moritz M, Pourmal S, Diallo A, Merz GE, Jang G, Bouhaddou M, Fossati A, Brilot AF, Diwanji D, Hernandez E, Herrera N, Kratochvil HT, Lam VL, Li F, Li Y, Nguyen HC, Nowotny C, Owens TW, Peters JK, Rizo AN, Schulze-Gahmen U, Smith AM, Young ID, Yu Z, Asarnow D, Billesbølle C, Campbell MG, Chen J, Chen KH, Chio US, Dickinson MS, Doan L, Jin M, Kim K, Li J, Li YL, Linossi E, Liu Y, Lo M, Lopez J, Lopez KE, Mancino A, Moss FR, Paul MD, Pawar KI, Pelin A, Pospiech TH, Puchades C, Remesh SG, Safari M, Schaefer K, Sun M, Tabios MC, Thwin AC, Titus EW, Trenker R, Tse E, Tsui TKM, Wang F, Zhang K, Zhang Y, Zhao J, Zhou F, Zhou Y, Zuliani-Alvarez L, QCRG Structural Biology Consortium , Agard DA, Cheng Y, Fraser JS, Jura N, Kortemme T, Manglik A, Southworth DR, Stroud RM, Swaney DL, Krogan NJ, Frost A, Rosenberg OS, Verba KA