# The integral membrane protease ZMPSTE24, lamin A processing, and the premature aging disease progeria

> **NIH NIH R35** · JOHNS HOPKINS UNIVERSITY · 2020 · $456,900

## Abstract

Project Summary
This project focuses on ZMPSTE24, an intriguing integral membrane zinc metalloprotease important for human
health and longevity. ZMPSTE24 plays a critical role in the proteolytic processing of the farnesylated CAAX
protein prelamin A, precursor of the nuclear scaffold component lamin A. Mutations in the genes encoding
either prelamin A or ZMPSTE24 that block cleavage cause the severe premature aging disorder Hutchinson-
Gilford Progeria syndrome (HGPS) and a set of related progeroid diseases in which an aberrant permanently
farnesylated form of lamin A is the “molecular culprit” that promotes aging-related symptoms. Importantly,
diminished prelamin A processing by ZMPSTE24 may also be a critical factor in normal physiological aging.
 My laboratory pioneered the study of ZMPSTE24 in the early years of this project. We discovered this
protease in yeast, where it is called Ste24, and showed that it has two distinct proteolytic activities in the
biogenesis of the mating pheromone a-factor (cleavage of the CAAX motif and a second upstream cleavage).
Importantly, we demonstrated that mammalian ZMPSTE24 performs these same cleavages in prelamin A
maturation. Through this sustained body of work, together with a powerful new humanized yeast system for
prelamin A cleavage recently developed in my laboratory, and our recent work showing a quality control role
for ZMPSTE24 in removing misfolded proteins from “clogged” translocons, we have at our fingertips a full
arsenal of tools, including a variety of biochemical and in vivo assays, cell lines, and disease alleles that will
facilitate the proposed studies. The recently published structure of human ZMPSTE24 and the nearly
superimposable yeast Ste24 revealed surprising features, defining ZMPSTE24/Ste24p as truly novel class of
intramembrane proteases. The seven transmembrane spans of ZMPSTE24/Ste24p form a voluminous water-
filled intramembrane chamber with the zinc metalloprotease catalytic site facing the chamber interior, so that
substrate access is restricted and must occur through one of several side portals. One major challenge in the
field is to establish how this novel intramembrane protease works. We propose to mechanistically
dissect human ZMPSTE24 and its substrate prelamin A to define precisely how proteolysis of prelamin A
occurs inside of an intramembrane chamber. We will identify features of ZMPSTE24 and prelamin A important
for substrate recognition, entry, binding, catalysis, and product release, and will determine the step at which
ZMPSTE24 and lamin A disease alleles malfunction. We will also deploy powerful designer screens possible
in yeast to identify new Ste24 substrates that may shed light on its mechanism. We will begin an exciting new
series of studies aimed at exploring a second major challenge, namely whether and how diminished
ZMPSTE24 activity and prelamin A accumulation may drive physiological aging. Together, these studies
will reveal fundamental principles rel...

## Key facts

- **NIH application ID:** 9970488
- **Project number:** 5R35GM127073-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Susan D. Michaelis
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $456,900
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970488

## Citation

> US National Institutes of Health, RePORTER application 9970488, The integral membrane protease ZMPSTE24, lamin A processing, and the premature aging disease progeria (5R35GM127073-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9970488. Licensed CC0.

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