UCSF

Research

Overview

How do cell surface proteomes change in health and disease? The Wells Lab addresses this question by applying protein and antibody engineering, mass spectrometry, and site-directed small molecule discovery to understand and disrupt human-disease-associated signalling processes.

The cell surface proteome—the surfaceome—is the communication and commerce hub of the cell, allowing it to exchange signals and nutrients with the extracellular environment and other cells. Once triggered, cellular receptors ignite internal signaling pathways that alter cell growth, differentiation, metabolic state, and even cell death or senescence. To understand and modulate these interwoven processes, our lab approaches these questions from three complementary angles:

  1. The extracellular proteome

  2. New tools for signaling

  3. Drug discovery

The extracellular proteome

diagram

This is a new, large-scale effort that uses cutting-edge proteomics, DNA-barcoded probes, and gene silencing to understand how and why the cell surfaceome is remodeled in diseases like cancer. We then employ our industrialized phage-antibody platform in the Antibiome Center (part of the Recombinant Antibody Network) to build antibodies to detect, modulate, and attack disease-related surface proteins on cells and in animals. Details: Extracellular Proteome.

New tools for signaling

This is a broad project to develop new engineered enzymes to identify the cellular substrates for proteases, kinases, ubiquitin ligases, or small molecule binding targets, and to selectively activate specific proteases, kinases, and CRISPR-driven processes using chemically-induced dimerization (CID) or light. Details: New Engineered Proteins for Signaling.

Drug discovery

This is a long-standing project to use Tethering®, a thiol-disulfide exchange technology, to trap novel drug fragments near existing or engineered cysteines in allosteric sites of enzymes (caspases, kinases, and phosphatases), or protein-protein interfaces (GPCR or cytokine receptors). Such fragments are useful mechanistic probes and starting points for drug discovery. Details: Site-directed Drug Discovery for Challenging Targets.


Tethering is a registered trademark of Sunesis Pharmaceuticals, Inc.