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 monthly and the digital edition weekly.

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.
 

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

Here’s the latest good and bad news about COVID-19 drugs
News

Here’s the latest good and bad news about COVID-19 drugs

May 26, 2022

After vaccines, antivirals and a monoclonal antibody are the next line of defense.

Zinc is a metal essential to life
News

Zinc is a metal essential to life

May 25, 2022

Scientists have discovered a protein that helps keep cells alive when zinc levels are low.

The mechanism of the monkeypox antiviral
News

The mechanism of the monkeypox antiviral

May 24, 2022

As monkeypox becomes an international concern, interest grows in tecovirimat; this smallpox drug targets a structural protein that helps wrap the virus in a second lipid bilayer.

Researchers investigate self-regulation of an enzyme with critical cellular functions
News

Researchers investigate self-regulation of an enzyme with critical cellular functions

May 24, 2022

They found that one mechanism of CK1 activity, and thus one mechanism of regulation, is the self-phosphorylation of a conserved amino acid residue in its catalytic domain.

What is monkeypox?
Science Communication

What is monkeypox?

May 23, 2022

A microbiologist explains what’s known about this smallpox cousin.

A simple method to determine phase preference of proteins on live cell membranes
Journal News

A simple method to determine phase preference of proteins on live cell membranes

May 22, 2022

“The phase preference of molecules used to be difficult and time-consuming to establish. This new method, detected by chance, provides results in at most 15 minutes on live cells,” Thorsten Wohland said.