6.2 Membrane proteins: structure and function
4 min read•august 1, 2024
Membrane proteins are the workhorses of cell membranes, performing crucial tasks like signaling, , and adhesion. They come in various types, from embedded in the to that temporarily associate with the membrane surface.
Understanding membrane protein structure and function is key to grasping how cells communicate and maintain homeostasis. From that trigger signaling cascades to 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
- span the entire bilayer (ion channels, receptors)
- 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)
- 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)
- mediate the movement of molecules across the membrane (glucose transporters, ion pumps)
- facilitate the passive transport of ions or small molecules (potassium channels, aquaporins)
- catalyze chemical reactions at the membrane surface (adenylyl cyclase, receptor guanylyl cyclases)
- maintain cell shape and mediate cell-cell interactions (cadherins, integrins)
Secondary structure
- contain single or multiple helices spanning the membrane (rhodopsin, bacteriorhodopsin)
- consist of multiple β-strands forming a barrel-like structure (porins, voltage-dependent anion channels)
Membrane protein folding
Thermodynamic principles
- 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
- Individual helices or β-strands first insert into the membrane
- Inserted segments then assemble into the final tertiary structure
- facilitates co-translational insertion of nascent polypeptide chains
- Sec61 in eukaryotes and SecYEG in bacteria form a channel for insertion
- assist in folding and quality control
- BiP and calnexin in the endoplasmic reticulum (ER) ensure proper folding
- influence folding and stability
- adds sugar moieties to specific residues (asparagine, serine, threonine)
- 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
- provides high-resolution structures
- Requires the formation of well-ordered protein crystals
- Challenging for hydrophobic membrane proteins due to their inherent flexibility
- (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
- (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)
- 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
Key Terms to Review (36)
Anchored proteins: Anchored proteins are a type of membrane protein that are attached to the cell membrane through covalent bonds with lipid molecules or through interactions with other membrane components. This anchoring allows them to maintain a stable position within the membrane, playing crucial roles in various cellular functions such as signaling, structural support, and maintaining membrane integrity.
Channel proteins: Channel proteins are specialized membrane proteins that facilitate the transport of ions and molecules across the cell membrane by forming pores or channels. These proteins are essential for various cellular processes, allowing specific substances to pass through the lipid bilayer in a controlled manner, and play a critical role in maintaining homeostasis by regulating the movement of ions and small molecules in and out of cells.
Chaperone proteins: Chaperone proteins are specialized proteins that assist in the proper folding and assembly of other proteins, ensuring they achieve their functional three-dimensional structures. They play a crucial role in preventing misfolding and aggregation, which can lead to cellular dysfunction and disease. By stabilizing unfolded or partially folded polypeptides, chaperone proteins help maintain protein homeostasis within the cell.
Cryo-electron microscopy: Cryo-electron microscopy (cryo-EM) is a cutting-edge imaging technique that allows researchers to visualize biological specimens at near-atomic resolution by rapidly freezing samples in a vitreous ice state. This method is significant for studying complex biomolecular structures, enabling insights into their interactions and functions without the need for extensive sample preparation or crystallization.
Disulfide bond formation: Disulfide bond formation is a type of covalent bond that occurs between the sulfur atoms of two cysteine residues in proteins, leading to the stabilization of protein structures. This bond is crucial for maintaining the three-dimensional conformation of proteins, particularly in extracellular environments where conditions can vary widely. Disulfide bonds contribute to the overall stability and functionality of many membrane proteins, which often require rigid structures to perform their roles effectively within cellular membranes.
Endocytosis: Endocytosis is the process by which cells engulf external substances, bringing them into the cell by enclosing them in a membrane-bound vesicle. This mechanism is crucial for cellular organization as it allows cells to take in nutrients, signaling molecules, and other important factors while also regulating their internal environment and maintaining compartmentalization.
Enzymatic proteins: Enzymatic proteins, also known as enzymes, are biological catalysts that accelerate chemical reactions in living organisms without being consumed in the process. They are crucial for various metabolic processes, aiding in the transformation of substrates into products through specific active sites that lower the activation energy required for reactions to occur. Their structure is intricately linked to their function, with many being integral components of cell membranes where they facilitate processes like signal transduction and nutrient transport.
Exocytosis: Exocytosis is the process by which cells transport secretory products or waste materials out of the cell by using vesicles that fuse with the plasma membrane. This mechanism is crucial for cellular communication, hormone secretion, and the removal of cellular waste, highlighting its significance in maintaining cellular organization and function.
Fluid Mosaic Model: The fluid mosaic model describes the structure of cell membranes, illustrating them as a dynamic and flexible arrangement of various molecules, including lipids and proteins. This model emphasizes the fluidity of the membrane, where lipids can move laterally and proteins can float within or on the lipid bilayer, leading to a diverse and functional membrane architecture that is essential for cellular organization, communication, and compartmentalization.
Förster resonance energy transfer: Förster resonance energy transfer (FRET) is a physical phenomenon where energy is transferred non-radiatively from an excited donor molecule to an acceptor molecule through dipole-dipole interactions. This process is highly sensitive to the distance between the donor and acceptor, making it a powerful tool for studying molecular interactions and dynamics, especially in biological systems. FRET is often utilized in the analysis of biomolecular interactions, such as protein-protein interactions, and plays a crucial role in understanding the structure and function of membrane proteins.
Glycoproteins: Glycoproteins are molecules that consist of a protein backbone with one or more carbohydrate chains attached to them. These structures play critical roles in various biological processes, such as cell signaling, immune response, and the formation of cellular structures. The carbohydrate component can affect the protein's stability, activity, and interactions, linking glycoproteins closely to both proteins and carbohydrates.
Glycosylation: Glycosylation is the process of attaching carbohydrate moieties, or glycans, to proteins or lipids, which is crucial for the proper functioning of membrane proteins. This modification can affect protein folding, stability, and interactions with other molecules, making it a key factor in various biological processes such as cell signaling and immune response. Glycosylation not only contributes to the structural diversity of membrane proteins but also plays a significant role in their functionality and cellular recognition.
Integral proteins: Integral proteins are a type of membrane protein that are embedded within the lipid bilayer of cell membranes, playing critical roles in various cellular functions. They can extend across the entire membrane or partially penetrate it, allowing them to interact with both the internal and external environments of the cell. Their unique positioning enables them to facilitate transport, serve as receptors, and participate in cell signaling.
Ion channels: Ion channels are integral membrane proteins that facilitate the selective passage of ions across the cell membrane, crucial for various physiological processes. These channels are vital for maintaining cellular homeostasis, generating electrical signals in neurons, and enabling muscle contractions. Their ability to open and close in response to specific stimuli adds a layer of regulation to cellular signaling pathways.
Lipid bilayer: The lipid bilayer is a fundamental structure of cell membranes, consisting of two layers of phospholipids arranged tail-to-tail, creating a semi-permeable barrier that separates the interior of the cell from the external environment. This unique arrangement not only provides structural integrity but also facilitates the proper functioning of embedded proteins and plays a crucial role in maintaining cellular fluidity and signaling processes.
Lipid-anchored proteins: Lipid-anchored proteins are a type of membrane protein that are attached to the cell membrane via lipid molecules. These proteins play critical roles in cellular signaling, anchoring the protein to the membrane while allowing it to interact with other cellular components. The lipid attachment can be either covalent or non-covalent, which influences the protein's mobility and function within the membrane.
Membrane fluidity: Membrane fluidity refers to the viscosity of the lipid bilayer of cell membranes, which influences how freely lipids and proteins move within that layer. This property is essential for maintaining cellular functions such as signaling, transport, and the ability to change shape. The degree of fluidity can vary with temperature, lipid composition, and the presence of cholesterol, impacting the behavior of membrane proteins and overall cell functionality.
Membrane protein folding: Membrane protein folding refers to the process by which proteins that span the lipid bilayer of cellular membranes acquire their functional three-dimensional structures. This process is critical for the proper functioning of membrane proteins, which play essential roles in various cellular functions, including signaling, transport, and maintaining cell integrity. Proper folding ensures that these proteins can interact correctly with other molecules and perform their designated tasks within the membrane environment.
Nuclear Magnetic Resonance Spectroscopy: Nuclear magnetic resonance spectroscopy (NMR spectroscopy) is an analytical technique used to determine the structure of molecules by observing the magnetic properties of atomic nuclei. This method is particularly useful for studying the structure and dynamics of membrane proteins, as it provides insights into their conformation, interactions, and the effects of their lipid environment on function.
Patch-clamp electrophysiology: Patch-clamp electrophysiology is a sophisticated technique used to measure ionic currents flowing through individual ion channels in cell membranes. This method allows researchers to study the electrical properties of cells with high precision, giving insight into the behavior of membrane proteins and their roles in cellular function.
Peripheral proteins: Peripheral proteins are proteins that are loosely attached to the exterior or interior surfaces of cell membranes, rather than being embedded within the lipid bilayer. These proteins play essential roles in various cellular functions, such as signaling, maintaining cell shape, and facilitating communication between cells, highlighting their importance in the overall functionality of biological membranes.
Post-translational modifications: Post-translational modifications (PTMs) refer to the chemical alterations that proteins undergo after their translation from mRNA. These modifications can significantly influence a protein's function, localization, stability, and interaction with other biomolecules, making them crucial for cellular processes and overall protein activity.
Protein Folding: Protein folding is the process by which a polypeptide chain acquires its functional three-dimensional structure from a linear sequence of amino acids. This intricate process is crucial for the biological function of proteins, and it relates to various challenges in understanding how proteins reach their final forms and how misfolding can lead to diseases.
Protein-lipid interactions: Protein-lipid interactions refer to the various ways that proteins interact with lipids within biological membranes, influencing membrane structure, dynamics, and function. These interactions are crucial for the functionality of membrane proteins, as they can dictate how proteins are anchored in the membrane, how they fold, and how they interact with other cellular components. Understanding these interactions helps to clarify essential processes like signal transduction, transport, and energy conversion in cells.
Receptor Proteins: Receptor proteins are specialized membrane proteins that bind to signaling molecules, known as ligands, to initiate a cellular response. These proteins play a crucial role in communication between cells, allowing them to respond appropriately to external signals such as hormones, neurotransmitters, and environmental changes.
Receptor-ligand binding: Receptor-ligand binding refers to the specific interaction between a receptor protein on a cell membrane and a ligand, which is typically a signaling molecule such as a hormone, neurotransmitter, or drug. This binding is crucial for various cellular processes, including signal transduction, where the receptor activates internal cellular responses upon ligand attachment. The nature of this binding can influence the receptor's conformation, affecting how cells respond to external signals and ultimately impacting physiological functions.
Selective permeability: Selective permeability is the property of cell membranes that allows certain substances to pass through while blocking others. This characteristic is vital for maintaining homeostasis within the cell, as it enables the selective entry and exit of ions, nutrients, and waste products. It is largely dependent on the structure and function of membrane proteins, which facilitate or restrict transport mechanisms across the lipid bilayer.
Signal Transduction: Signal transduction is the process by which cells convert external signals into a functional response, allowing them to react to their environment. This complex communication involves various biomolecules, including proteins and lipids, which play critical roles in relaying signals across cellular compartments, ultimately influencing cell behavior, metabolism, and function.
Structural Proteins: Structural proteins are a category of proteins that provide support, shape, and stability to cells and tissues. They play a crucial role in maintaining the integrity of cellular structures, forming the framework for biological tissues, and contributing to the overall architecture of organisms, particularly in the context of membrane proteins that organize and stabilize cellular membranes.
Translocon complex: The translocon complex is a multi-protein structure located in the membrane of the endoplasmic reticulum (ER) that facilitates the translocation of nascent polypeptides across the ER membrane. This complex is crucial for protein synthesis and targeting, as it ensures that proteins are properly inserted into the ER or secreted outside the cell. By forming a channel through which polypeptides can pass, the translocon plays a vital role in maintaining cellular function and protein homeostasis.
Transmembrane proteins: Transmembrane proteins are integral membrane proteins that span across the lipid bilayer of cell membranes, playing crucial roles in various cellular functions. They consist of one or more hydrophobic regions that interact with the lipid environment, allowing them to remain embedded within the membrane. These proteins can function as channels, transporters, receptors, or enzymes, facilitating communication and transport between the cell's interior and exterior.
Transport: Transport refers to the movement of substances across cell membranes, allowing cells to maintain homeostasis and communicate with their environment. This process is essential for cellular function and involves various mechanisms, including passive and active transport, facilitated by membrane proteins that play critical roles in regulating what enters and exits the cell.
Transporter proteins: Transporter proteins are specialized membrane proteins that facilitate the movement of ions, small molecules, and larger substrates across cellular membranes. They play a critical role in maintaining cellular homeostasis by regulating the concentrations of various substances inside and outside the cell, which is essential for processes such as nutrient uptake, waste removal, and signal transduction.
X-ray crystallography: X-ray crystallography is a powerful technique used to determine the atomic structure of crystalline materials by analyzing the diffraction patterns produced when X-rays are scattered by the crystal lattice. This method is essential in revealing detailed information about biomolecular structures, which is crucial for understanding their function and interactions.
α-helical membrane proteins: α-helical membrane proteins are integral membrane proteins characterized by their structure, which contains one or more α-helices that span the lipid bilayer of cell membranes. These proteins play crucial roles in various cellular functions, including transport, signaling, and providing structural integrity to membranes, and their helical nature allows them to interact favorably with the hydrophobic environment of the lipid bilayer.
β-barrel membrane proteins: β-barrel membrane proteins are a class of proteins that form cylindrical structures composed of β-sheets, which span the lipid bilayer of cellular membranes. These proteins play crucial roles in various biological functions, including transport, signaling, and forming channels that allow the passage of molecules across the membrane.