# Biophysical and structural analysis of the herpesviral nuclear budding machinery

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2020 · $621,899

## Abstract

PROJECT SUMMARY/ABSTRACT
Herpesviruses are double-stranded-DNA enveloped viruses that are among the most complex viruses infecting
animals. This proposal focuses on nuclear egress, a critical, conserved step in the assembly and release of
progeny virions during which nucleocapsids are translocated from the nucleus into the cytoplasm where they
mature into infectious virions. The viral nuclear egress complex (NEC) is the key player in this process. Using
in vitro model systems, we previously discovered that the NEC is a complete, virally encoded membrane
budding machine that operates at the nuclear envelope. However, a major barrier to understanding nuclear
egress is the lack of knowledge of how the NEC generates membrane curvature that results in budding. The
long-term goal of this research is to elucidate the detailed mechanism of herpesvirus nuclear egress, both to
gain a fundamental knowledge of this unusual process and to identify and characterize novel targets for
antiviral therapeutic design. This proposal is driven by the central hypothesis, based on substantial
preliminary data, that both NEC/membrane interactions and NEC oligomerization into a coat are the major
driving forces that enable negative membrane curvature formation and budding. The objective of this proposal
is to systematically dissect the NEC budding mechanism in Herpes Simples virus (HSV) by characterizing
essential protein/protein and protein/membrane interactions and budding intermediates by employing a
multidisciplinary approach, which includes the cutting-edge approaches of cryoelectron microscopy and
electron spin resonance. The scientific premise of the proposed work is that a comprehensive dissection of
the NEC-mediated formation of negative membrane curvature is essential for unraveling the unusual
mechanism of herpesviral nuclear egress and developing strategies to block it. Beyond viruses, this study will
expand our limited mechanistic understanding of the mechanisms of membrane deformation in general. The
proposal is innovative because it investigates an unusual mechanism, is guided by an original hypothesis, and
employs novel approaches. The proposal is significant because it aims to advance our mechanistic
understanding of an essential step in viral replication cycle with the goal of identifying new targets for
therapeutic interventions and because it provides an opportunity to develop models of negative curvature
formation, currently a black box.

## Key facts

- **NIH application ID:** 9942380
- **Project number:** 5R01AI147625-02
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Ekaterina Heldwein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $621,899
- **Award type:** 5
- **Project period:** 2019-06-05 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942380

## Citation

> US National Institutes of Health, RePORTER application 9942380, Biophysical and structural analysis of the herpesviral nuclear budding machinery (5R01AI147625-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9942380. Licensed CC0.

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