# ER-to-Golgi transport of coagulation factors V and VIII

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $402,500

## Abstract

ER-to-Golgi transport of coagulation factors V and VIII
 Coagulation factor V (FV) and factor VIII (FVIII) are both secreted glycoproteins that share pivotal roles in
both hemostasis and thrombosis. Genetic deficiency of FVIII results in hemophilia A, which affects ~1 in 5000
males. On the other hand, a gain-of-function mutation in FV (FV Leiden) and increased FVIII activity are major
risk factors for venous thrombosis, which affects ~1:1,000 individuals in the US per year. Although many
secreted proteins (referred to as cargo) are believed to require transport receptors for efficient endoplasmic
reticulum (ER)-to-Golgi transport, only a limited number of such receptors have been described, mostly in
yeast. Evidence for the existence of mammalian cargo receptors came unexpectedly from studies of the
human genetic disorder combined deficiency of FV and FVIII (F5F8D), which identified mutations in LMAN1
and MCFD2 as the cause of the disorder. F5F8D is a rare bleeding disorder characterized by the reduction of
both FV and FVIII to 5-30% of normal. LMAN1 and MCFD2 form a Ca2+-dependent protein complex in the ER-
Golgi intermediate compartment that interacts with FV and FVIII, suggesting that the LMAN1-MCFD2 complex
is a cargo receptor required for efficient transport of FV and FVIII from the ER to the Golgi. The requirement of
both a transmembrane component (LMAN1) and a soluble cofactor (MCFD2) suggests a more sophisticated
mechanism for cargo trafficking in higher eukaryotes, and could represent a paradigm for the organization of
other mammalian cargo receptors. In this proposal, we will study the mechanism of receptor-mediated ER-to-
Golgi transport of FV and FVIII. In aim 1, we will identify N-linked glycosylation sites on FV/FVIII that interact
with LMAN1, investigate Ca2+ in regulating the binding and release of cargo, and increase in vitro FVIII
production by enhancing the LMAN1-MCFD2 secretion pathway. In aim 2, we will identify sorting signals in
FVIII that are recognized by MCFD2, investigate the ER-to-Golgi transport deficiency as a novel mechanism of
hemophilia A, and identify other components/alternative pathways that control FV/FVIII trafficking. In aim 3, we
will test the LMAN1-MCFD2 secretion pathway as a therapeutic target for thrombophilia and create a mouse
model to characterize the role of B domain in FVIII biosynthesis and LMAN1-MCFD2 mediated secretion in
vivo. Results will not only answer fundamental questions regarding the mechanism of LMAN1-MCFD2
receptor-mediated secretion of FV and FVIII, but will also provide fundamental new insight into general
mechanism of mammalian ER-to-Golgi protein transport. The findings will have practical importance for
improving FVIII expression and may expedite the eventual goal of somatic cell gene therapy for hemophilia A,
as well as new approaches to limiting FV and FVIII production in prothrombotic states.

## Key facts

- **NIH application ID:** 10418635
- **Project number:** 5R01HL094505-13
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Bin Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2008-12-26 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10418635

## Citation

> US National Institutes of Health, RePORTER application 10418635, ER-to-Golgi transport of coagulation factors V and VIII (5R01HL094505-13). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10418635. Licensed CC0.

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