# Structural and Functional Roles of the Membrane-Related Components of Single-Pass Membrane Proteins

> **NIH NIH R35** · HARVARD MEDICAL SCHOOL · 2021 · $441,090

## Abstract

PROJECT SUMMARY
My laboratory investigates the structural and functional roles of the transmembrane (TM) and membrane-
proximal (MP) regions of immune receptors and viral fusion proteins. The single-pass transmembrane (TM)
proteins account for the vast majority of signaling receptors on the cell surface, and due to the lack of structural
information, the TM/MP regions are often the missing link in our understanding of how extracellular ligand binding
is translated to the activation of intracellular signaling pathways. TM and MP regions of single-pass membrane
proteins are extremely difficult to visualize. We have developed an effective NMR/biochemistry technology
platform for visualizing these regions and found that they can have surprisingly important biological function other
than membrane anchoring. We find that a few receptors in the tumor necrosis factor receptor superfamily
(TNFRSF) exhibit a previously unknown phenomenon that their transmembrane domains (TMDs) alone can
oligomerize in membrane and drive receptor clustering and activation. In another finding, the TM region of the
HIV-1 envelope spike form defined trimeric structure that can strongly influence the antigenicity of the
ectodomain of the spike currently being used for vaccine development. The above few examples already suggest
the enormous potential of uncovering the membrane regions of type I/II membrane proteins in discovering new
biological mechanisms, which is the motivation for the proposed research. In the next five years, we will continue
to explore the structure and function of TM regions with three specific goals. (1) We will further examine the
mechanism of TMD-mediated receptor clustering and activation for other members of the TNFRSF and test the
generality of this new concept in receptor biology. (2) We will explore the function of TMD oligomerization in the
signaling mechanism of the  chain cytokine receptors, for which the membrane regions are completely unknown.
(3) We will continue to examine the TM and MP regions of other viral fusion proteins such as that of SIV and
coronavirus, for understanding how the membrane-interacting components of the fusion proteins stabilize the
prefusion state of the envelope spikes and for revealing unique structural features that may be used for testing
mechanistic hypotheses of viral membrane fusion.

## Key facts

- **NIH application ID:** 10167495
- **Project number:** 1R35GM140887-01
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** JAMES Jeiwen CHOU
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $441,090
- **Award type:** 1
- **Project period:** 2021-05-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167495

## Citation

> US National Institutes of Health, RePORTER application 10167495, Structural and Functional Roles of the Membrane-Related Components of Single-Pass Membrane Proteins (1R35GM140887-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10167495. Licensed CC0.

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