# EFR3A, an Intriguing Gene, and Protein with a Scaffolding Function

## TL;DR

EFR3A is a poorly understood protein involved in cell signaling and linked to various diseases, making it a promising target for future research.

## Contribution

This review highlights EFR3A's scaffolding function and its newly uncovered interaction with flotillin-2.

## Key findings

- EFR3A is linked to neurological, cardiovascular, and tumor-related disorders.
- EFR3A anchors the phosphatidylinositol 4-kinase A complex to the plasma membrane.
- EFR3A interacts with flotillin-2, possibly regulating membrane raft domains.

## Abstract

The EFR3 (Eighty-Five Requiring 3) protein and its homologs are rather poorly understood eukaryotic plasma membrane peripheral proteins. They belong to the armadillo-like family of superhelical proteins. In higher vertebrates two paralog genes, A and B were found, each expressing at least 2–3 protein isoforms. EFR3s are involved in several physiological functions, mostly including phosphatidyl inositide phosphates, e.g., phototransduction (insects), GPCRs, and insulin receptors regulated processes (mammals). Mutations in the EFR3A were linked to several types of human disorders, i.e., neurological, cardiovascular, and several tumors. Structural data on the atomic level indicate the extended superhelical rod-like structure of the first two-thirds of the molecule with a typical armadillo repeat motif (ARM) in the N-terminal part and a triple helical motif in its C-terminal part. EFR3s’ best-known molecular function is anchoring the giant phosphatidylinositol 4-kinase A complex to the plasma membrane crucial for cell signaling, also linked directly to the KRAS mutant oncogenic function. Another function connected to the newly uncovered interaction of EFR3A with flotillin-2 may be the participation of the former in the organization and regulation of the membrane raft domain. This review presents EFR3A as an intriguing subject of future studies.