6.2 Membrane proteins: structure and function

Membrane proteins are the workhorses of cell membranes, performing crucial tasks like signaling, transport, and adhesion. They come in various types, from integral proteins embedded in the lipid bilayer to peripheral proteins that temporarily associate with the membrane surface.

Understanding membrane protein structure and function is key to grasping how cells communicate and maintain homeostasis. From receptor proteins that trigger signaling cascades to ion channels that control cellular electricity, these proteins are essential for life's most fundamental processes.

Membrane protein types

Structural classification

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• Integral membrane proteins are permanently embedded within the lipid bilayer
  • Transmembrane proteins span the entire bilayer (ion channels, receptors)
  • Anchored proteins are partially embedded (cytochrome c)
• Peripheral membrane proteins are temporarily associated with the membrane surface
  • Interact with integral proteins or lipid head groups (G proteins, protein kinases)
• Lipid-anchored proteins are covalently attached to lipid molecules
  • Glycosylphosphatidylinositol (GPI) anchors proteins to the membrane (alkaline phosphatase, Thy-1)

Functional classification

• Receptor proteins bind extracellular ligands and initiate intracellular signaling (GPCRs, RTKs)
• Transporter proteins mediate the movement of molecules across the membrane (glucose transporters, ion pumps)
• Channel proteins facilitate the passive transport of ions or small molecules (potassium channels, aquaporins)
• Enzymatic proteins catalyze chemical reactions at the membrane surface (adenylyl cyclase, receptor guanylyl cyclases)
• Structural proteins maintain cell shape and mediate cell-cell interactions (cadherins, integrins)

Secondary structure

• α-helical membrane proteins contain single or multiple helices spanning the membrane (rhodopsin, bacteriorhodopsin)
• β-barrel membrane proteins consist of multiple β-strands forming a barrel-like structure (porins, voltage-dependent anion channels)

Membrane protein folding

Thermodynamic principles

• Membrane protein folding is driven by the hydrophobic effect
  • Nonpolar amino acid residues are buried within the lipid bilayer
  • Polar and charged residues face the aqueous environment
• Minimizing the exposure of hydrophobic residues to water is a key driving force for folding

Folding and insertion mechanisms

• Two-stage model of membrane protein folding
  • Individual helices or β-strands first insert into the membrane
  • Inserted segments then assemble into the final tertiary structure
• Translocon complex facilitates co-translational insertion of nascent polypeptide chains
  • Sec61 in eukaryotes and SecYEG in bacteria form a channel for insertion
• Chaperone proteins assist in folding and quality control
  • BiP and calnexin in the endoplasmic reticulum (ER) ensure proper folding
• Post-translational modifications influence folding and stability
  • Glycosylation adds sugar moieties to specific residues (asparagine, serine, threonine)
  • Disulfide bond formation between cysteine residues stabilizes tertiary structure

Membrane protein roles

Cell signaling

• Receptor proteins bind extracellular ligands and initiate intracellular signaling cascades
  • G protein-coupled receptors (GPCRs) activate G proteins upon ligand binding (β2-adrenergic receptor, rhodopsin)
  • Receptor tyrosine kinases (RTKs) dimerize and autophosphorylate upon ligand binding (EGF receptor, insulin receptor)
• Enzymatic membrane proteins catalyze reactions involved in signaling
  • Receptor guanylyl cyclases produce cGMP as a second messenger (atrial natriuretic peptide receptor)
  • Adenylyl cyclases generate cAMP in response to GPCR activation (β2-adrenergic receptor signaling)

Transport and channels

• Ion channels facilitate the passive transport of ions across the membrane
  • Voltage-gated channels open or close in response to changes in membrane potential (sodium channels, potassium channels)
  • Ligand-gated channels open upon binding of specific ligands (nicotinic acetylcholine receptor, GABA receptor)
• Transporters mediate the active or passive movement of molecules
  • Uniporters transport a single solute down its concentration gradient (glucose transporters)
  • Symporters co-transport two solutes in the same direction (sodium-glucose cotransporter)
  • Antiporters exchange two solutes in opposite directions (sodium-calcium exchanger)

Cell adhesion and structure

• Adhesion proteins mediate cell-cell and cell-extracellular matrix interactions
  • Cadherins form calcium-dependent homophilic interactions between cells (E-cadherin in epithelial tissues)
  • Integrins bind to extracellular matrix components and link to the cytoskeleton (α5β1 integrin binds fibronectin)
• Structural proteins maintain cell shape and organize membrane domains
  • Spectrin and ankyrin form a submembrane cytoskeleton in erythrocytes
  • Caveolins and flotillins organize lipid rafts and caveolae

Membrane protein study techniques

Structural determination

• X-ray crystallography provides high-resolution structures
  • Requires the formation of well-ordered protein crystals
  • Challenging for hydrophobic membrane proteins due to their inherent flexibility
• Cryo-electron microscopy (cryo-EM) enables structure determination in native lipid environment
  • Eliminates the need for protein crystallization
  • Allows for the study of large membrane protein complexes (ribosome-translocon complex)
• Nuclear magnetic resonance (NMR) spectroscopy allows for the study of protein dynamics and interactions
  • Suitable for smaller membrane proteins or domains
  • Can be performed in solution or membrane-mimetic environments (micelles, nanodiscs)

Functional and dynamic studies

• Fluorescence spectroscopy techniques probe conformational changes and interactions
  • Förster resonance energy transfer (FRET) measures distance between fluorophore-labeled residues (GPCR activation studies)
  • Single-molecule fluorescence tracks individual protein molecules in real-time (ion channel gating, transporter dynamics)
• Patch-clamp electrophysiology measures electrical currents across the membrane
  • Allows for the study of ion channel gating and conductance
  • Can be combined with mutagenesis to identify key residues in channel function
• Biochemical assays provide insights into protein function and kinetics
  • Ligand binding assays determine the affinity and specificity of receptor-ligand interactions
  • Enzyme kinetics experiments measure the catalytic activity of membrane-associated enzymes
  • Transport assays monitor the movement of substrates across the membrane