# Structural basis of apoptotic scrambling

> **NIH AI R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2026 · $637,820

## Abstract

ABSTRACT
Every day ~50 billion cells undergo apoptosis, or programmed cell death. Efficient recognition and clearance of
these cells is critical for tissue homeostasis in physiology and for its recovery following disease. Initiation of the
apoptotic cascade triggers activation of phospholipid scramblases that externalize the lipid phosphatidylserine
(PS) in the outer leaflet of the plasma membrane. Recognition of PS by dedicated receptors (PSRs) on immune
cells is the first and critical step in the clearance of apoptotic cells. Immune cells with activated PSRs create an
immunosuppressive environment that can be exploited by pathogens exposing PS in an immune-camouflage
strategy called apoptotic mimicry. Recent studies implicated members of the XKR protein family in apoptotic
scrambling. Dysfunction of XKR proteins results in an inflammatory environment and autoimmune disorders
while their uncontrolled activation favors oncogenesis and facilitate viral entry. Thus, it is critical to elucidate the
molecular mechanisms of XKR function and regulation to understand their physiological roles and their
association with pathology. Currently, only structures of non-functional XKR proteins are available, hindering our
understanding of how these protein mediate PS externalization. In preliminary experiments we show that two
XKR homologues, CED-8 from C. elegans and human XKR4, scramble lipids. Using cryogenic electron
microscopy, we determined the 3.55 Å resolution structure of hXKR4 in a novel, likely active conformation,
providing insights into a potential mechanism for lipid transport. In our 1st aim, we propose to determine the
structures of hXKR4 and CED-8 in different conformations and functional states to determine the molecular
bases of XKR activation. We will use our newly developed biochemical assays to probe and elucidate the
functional implications of these structures. The physiological implications of these mechanisms will be tested in
cell-based measurements. Our

## Key facts

- **NIH application ID:** 11239806
- **Project number:** 5R01AI178180-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Alessio  Accardi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** AI
- **Fiscal year:** 2026
- **Award amount:** $637,820
- **Award type:** 5
- **Project period:** 2024-02-01T00:00:00 → 2028-12-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11239806

## Citation

> US National Institutes of Health, RePORTER application 11239806, Structural basis of apoptotic scrambling (5R01AI178180-03). Retrieved via AI Analytics 2026-07-13 from https://api.ai-analytics.org/grant/nih/11239806. Licensed CC0.

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