Lipid News

A molecular determinant of membrane protein targeting

Himani Dey Abdur Rahaman
By Himani Dey and Abdur Rahaman
Sept. 22, 2021

Specific membrane lipids serve not only as constituents of membrane architecture but also as modulators of membrane-interacting proteins during diverse cellular processes such as cell signalling, receptor-mediated endocytosis, apoptosis, mitochondrial fusion and maintenance of mitochondrial potential. Primarily due to their varying acyl side chains, these lipids assume various shapes including cylinders and cones.

Himani Dey
The diagram shows targeting/partitioning of Drp6 to the nuclear membrane. The membrane binding domain (red) of Drp6 specifically interacts with cardiolipin (blue) present on the nuclear membrane.

Most proteins residing in or on membrane bilayers are targeted to their destination co-translationally, whereas specific proteins involved in membrane remodeling — such as clathrin, caveolin, BAR-domain carrying proteins, Arfs, epsin, flotillin and dynamins — are recruited to their sites of action post-translationally. The latter proteins are known to interact with their target membranes by electrostatic interaction or by inserting their hydrophobic domains or amphipathic helices into the membrane bilayer.

Dynamin superfamily proteins are large GTPases that rely on their ability to form uniformly organised self-assembled structures to generate a scaffold to remodel their underlying membranes. These proteins facilitate the generation of membrane curvature required for membrane fission or fusion. Targeting of dynamins to their target membranes depends on the recognition and clustering of specific lipids. For example, dyanmin1 recognizes PI(4,5)P2 in binding to endocytic vesicles on the plasma membrane, while OPA1 recognises cardiolipin on the opposing inner mitochondrial membranes to cause membrane fusion.

These processes require a dedicated stretch of membrane-binding residues. Binding of classical dynamins to the membrane is mediated by a conventional membrane-binding domain called a pleckstrin homology, or PH, domain. However, a subclass of dynamin family members known as dynamin-related proteins lacks a PH domain and instead contains a B-insert for membrane recognition.

In a recent study, the nuclear envelope–localized dynamin-related protein Drp6 in Tetrahymena has been shown to depend on cardiolipin for the translocation to its target membrane. Though Drp6 interacts with three distinct phospholipids (phosphatidic acid, phosphatidylserine and cardiolipin), mutation of a critical isoleucine residue (Ile553) in the membrane-binding domain of Drp6 inhibits its interaction specifically with cardiolipin and abrogates nuclear membrane recruitment. This study establishes a role for a single amino acid residue in determining target membrane specificity through interaction with a specific lipid. Though the membrane-binding domain (PH domain or B-insert) and interacting lipid of several dynamin family proteins have been identified, researchers do not yet know the mechanism by which these proteins determine target membrane specificity.

Partitioning of proteins to different compartments is emerging as a robust mechanism for spatiotemporal regulation of protein function. Although a large number of studies demonstrate the importance of hydrophobic and electrostatic interactions in determining target membrane binding, researchers have not yet determined how proteins discriminate different phospholipids. Detailed structural analysis of protein–lipid complexes using techniques such as high-resolution cryo-electron microscopy or X-ray crystallography is likely to shed light on the precise mechanism of membrane protein targeting.

Enjoy reading ASBMB Today?

Become a member to receive the print edition four times a year and the digital edition monthly.

Learn more
Himani Dey
Himani Dey

Himani Dey is a Ph.D. student in Abdur Rahaman’s lab in the School of Biological Sciences at the National Institute of Science Education and Research in India.
 

Abdur Rahaman
Abdur Rahaman

Abdur Rahaman is a Reader F in the School of Biological Sciences at the National Institute of Science Education and Research in India.
 

Related articles

Cholesterol lures in coronavirus
Marissa Locke Rottinghaus
A surprising modification lowers the lipid binding affinity of a membrane trafficking protein
Jefferson Knight, Colin T. Shearn & Cisloynny Beauchamp–Pérez
Elusive zebrafish enzyme in lipid secretion
Isabel Casas & Emily Ulrich
From the journals: JBC
Ken Farabaugh

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

RA patient blood reveals joint innerworkings
Journal News

RA patient blood reveals joint innerworkings

July 25, 2025

Researchers in the Netherlands use mass spectrometry to compare the proteome of plasma and synovial fluid in rheumatoid arthritis patients and find a correlation. Read more about this recent paper in Molecular & Cellular Proteomics.

Hope for a cure hangs on research
Essay

Hope for a cure hangs on research

July 17, 2025

Amid drastic proposed cuts to biomedical research, rare disease families like Hailey Adkisson’s fight for survival and hope. Without funding, science can’t “catch up” to help the patients who need it most.

Before we’ve lost what we can’t rebuild: Hope for prion disease
Feature

Before we’ve lost what we can’t rebuild: Hope for prion disease

July 15, 2025

Sonia Vallabh and Eric Minikel, a husband-and-wife team racing to cure prion disease, helped develop ION717, an antisense oligonucleotide treatment now in clinical trials. Their mission is personal — and just getting started.

Defeating deletions and duplications
News

Defeating deletions and duplications

July 11, 2025

Promising therapeutics for chromosome 15 rare neurodevelopmental disorders, including Angelman syndrome, Dup15q syndrome and Prader–Willi syndrome.

Using 'nature’s mistakes' as a window into Lafora disease
Feature

Using 'nature’s mistakes' as a window into Lafora disease

July 10, 2025

After years of heartbreak, Lafora disease families are fueling glycogen storage research breakthroughs, helping develop therapies that may treat not only Lafora but other related neurological disorders.

Cracking cancer’s code through functional connections
News

Cracking cancer’s code through functional connections

July 2, 2025

A machine learning–derived protein cofunction network is transforming how scientists understand and uncover relationships between proteins in cancer.