Lipid-Linked Membrane Proteins: Structure, Types, and Functions

Concept: Lipid-Linked Membrane Proteins

Introduction to Lipid-Linked Membrane Proteins

Lipid-linked membrane proteins are proteins covalently anchored to one or more lipid groups within the bilayer. These proteins exhibit a reversible and relatively weak association with the membrane compared to integral proteins. Some types are exclusively linked to one side of the membrane, contributing to membrane asymmetry and specialized cellular functions.

• Lipid-linked proteins are not embedded within the membrane but are attached via lipid anchors.

• They play crucial roles in signaling, membrane trafficking, and protein localization.

Types of Lipid-Linked Membrane Proteins

There are four major types of lipid-linked membrane proteins, classified by the nature of their lipid anchor and their location within the membrane.

Lipid-Linked Membrane Proteins	Lipid Group	Linkage to Protein	Side of Membrane
1) Prenylated proteins	Farnesyl, Geranylgeranyl	Thioether linkage to Cys (C-terminal)	Inner surface
2) Fatty acylated proteins	Myristoyl, Palmitoyl	Amide (myristoyl) or thioester (palmitoyl) linkage to Gly or Cys	Inner surface
3) Glycosylphosphatidylinositol (GPI)-anchored proteins	Phosphatidylinositol	Amide linkage to C-terminal residue	Outer surface
4) Phospholipid-anchored proteins	Phosphatidylethanolamine, Phosphatidylserine	Amide or ester linkage	Inner surface

Key Features and Functions

• Prenylation: Addition of isoprenoid groups (farnesyl or geranylgeranyl) to C-terminal cysteine residues. Important for protein localization and signaling.

• Myristoylation: Attachment of myristic acid (C14:0) to the N-terminal glycine via an amide bond. Common in proteins involved in signal transduction.

• Palmitoylation: Addition of palmitic acid (C16:0) to cysteine residues via thioester bonds. This modification is reversible and regulates membrane association.

• GPI Anchoring: Proteins are linked to the membrane via a glycosylphosphatidylinositol anchor, typically found on the extracellular surface and involved in cell recognition and signaling.

Practice Questions and Explanations

These questions help reinforce understanding of lipid-linked membrane proteins:

1. Prenylated proteins:

   • Are not integral membrane proteins.

   • Contain thioether linkages to single-chain fatty acids.

   • Are found on the inner surface of the membrane.

2. Location of Lipid-Linked Proteins:

   • GPI-anchored proteins are primarily located on the exterior surface of the membrane.

   • Myristoylated and palmitoylated proteins are typically found on the inner surface.

3. Reversible Lipid Anchor Modifications:

   • Palmitoylation is readily reversible with the help of thioesterases.

   • Myristoylation is generally irreversible.

Examples and Applications

• Ras proteins are prenylated and play a key role in cell signaling.

• Src kinase is myristoylated, which is essential for its membrane localization and function.

• GPI-anchored proteins include enzymes and receptors involved in immune response and cell adhesion.

Summary Table: Lipid Anchor Types and Properties

Anchor Type	Bond Type	Reversibility	Membrane Side
Prenylation	Thioether	Irreversible	Inner
Myristoylation	Amide	Irreversible	Inner
Palmitoylation	Thioester	Reversible	Inner
GPI Anchoring	Amide	Irreversible	Outer

Key Equations and Chemical Linkages

• Thioester linkage (Palmitoylation): $\text{Protein-SH} + \text{Palmitoyl-CoA} \rightarrow \text{Protein-S-palmitoyl} + \text{CoA-SH}$

• Amide linkage (Myristoylation): $\text{Protein-NH}_2 + \text{Myristoyl-CoA} \rightarrow \text{Protein-N-myristoyl} + \text{CoA-SH}$

• Thioether linkage (Prenylation): $\text{Protein-SH} + \text{Farnesyl/geranylgeranyl pyrophosphate} \rightarrow \text{Protein-S-prenyl} + \text{PP}_i$

Additional info: Lipid-linked proteins are essential for dynamic cellular processes, including signal transduction, membrane trafficking, and protein sorting. Their reversible association with membranes allows for rapid cellular responses to environmental changes.