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Protein Structure and Function
By Gregory A Petsko and Dagmar Ringe
Updates
Updates – 2007-2008
Chapter 1: From Sequence to Structure
Active transport proteins
U1-12 Active Transport: ATP-Binding Cassette Transporters [Full Text] [PDF]
-The energy of ATP hydrolysis can be used to pump substrates across membranes
-ABC transporters transport an enormous variety of substrates
-The nucleotide-binding domain of the ABC transporters dimerizes to bind ATP
-The ABC transporters may work by a mechanism of alternating conformational states similar to that of the MFS transporters
U1-13 Active Transport: Bacterial Multidrug Resistance [Full Text] [PDF]
-Bacteria contain secondary active transporters that pump drugs out of the cell in exchange for the inward transport of protons
-In complex with substrate, AcrB is an asymmetrical trimer
-RMD proteins appear to operate by a proton-driven alternating-access mechanism
Chapter 2: From Structure to Function
Protein interactions – Chapter 3 on Principles and Mechanisms of Protein Interactions from Cell Signaling by Lim, Mayer and Pawson
3-0 Overview: Binding Interactions between Signaling Proteins [Full Text] [PDF]
-Changes in protein binding are important for transmitting signals
-Changes in protein binding have both direct and indirect functional consequences
-Protein binding is regulated in many ways in the cell
3-1 Properties of Protein–Protein Interactions [Full Text] [PDF]
-Protein binding can be mediated by broad interaction surfaces or by short, linear peptides
-Modular protein-binding and lipid-binding domains are important in signaling
-Dynamic protein assemblies that transduce signals have different properties from stable macromolecular complexes
3-2 Affinity and Specificity [Full Text] [PDF]
-The affinity and specificity of an interaction determine how likely it is to occur in the cell
-Specificity is determined by the relative affinities of competing interactions
-The likelihood of a protein interaction in a cell depends on the cellular and molecular context
3-3 The Dissociation Constant and Binding Energy [Full Text] [PDF]
-The strength of a binding interaction is defined by the dissociation constant (Kd)
-The dissociation constant is related to the binding energy of the interaction
3-4 Binding Kinetics [Full Text] [PDF]
-The dissociation constant is also related to rates of binding and unbinding
-The apparent Kd can be strongly affected by the local cellular environment and other binding partners
3-5 Tuning of Affinities and Specificities for Biological Function [Full Text] [PDF]
-Ideal affinity and specificity depends on biological function and ligand concentrations
-There are functional constraints on interaction affinities and specificities
3-6 Mechanisms for Tuning Interaction Affinity and Specificity [Full Text] [PDF]
-Affinity and specificity can be independently modulated
-Positive discrimination can increase affinity without increasing specificity
-Negative discrimination can increase specificity without increasing affinity
3-7 Cooperative Binding [Full Text] [PDF]
-A variety of experimental methods are used to detect protein–protein interactions
-Cooperativity involves the coupled binding of multiple ligands
-Diverse molecular mechanisms underlie cooperativity
-Cooperative binding has a variety of functional consequences
3-8 Mapping Protein–Protein Interactions [Full Text] [PDF]
-Interacting proteins can be identified by isolating protein complexes from cell extracts
-Binding partners can be identified by screening large libraries of genes
-Direct protein–protein interactions can be detected by solid-phase screening
3-9 Analyzing Protein–Protein Interactions in Living Cells [Full Text] [PDF]
-Interactions can be visualized and quantified in living cells
-Fluorescent protein tags are used to locate and track proteins in cells
-Protein–protein interactions can be visualized directly in living cells
3-10 Experimental Determination of Quantitative Binding Parameters [Full Text] [PDF]
-Analytical methods can determine quantitative binding parameters
-Equilibrium binding studies can be used to determine the dissociation constant
-Rates of binding and dissociation, and thermodynamic binding parameters, can be determined experimentally
-Binding parameters are important for quantitative modeling of signaling pathways
Chapter 3: Control of Protein Function
Protein phosphatases
U3-3 Protein Phosphatases: Structure and Catalytic Mechanisms [Full Text] [PDF]
-Protein phosphatases fall into several groups
-Protein serine/threonine phosphatases are metalloproteins
-Protein tyrosine phosphatases function via a phosphoenzyme intermediate and include receptors as well as cytoplasmic enzymes
-Some phosphoinositide phosphatases are related to protein tyrosine phosphatases
U3-4 Protein Phosphatases: Pathways and Regulation [Full Text] [PDF]
-Phosphatases function in conjunction with protein kinases to regulate signaling
Updates – 2006-2007
Chapter 1: From Sequence to Structure
Membrane proteins
U1-6 Membrane Protein Structure and Function [Full Text] [PDF]
-Membrane proteins are essential for intercellular communication, cellular recognition, and the uptake of nutrients
-The structures of membrane proteins are slowly being determined
U1-7 Membrane Proteins:Topology [Full Text] [PDF]
-Aromatic residues in transmembrane proteins are concentrated in a belt at the interface with membrane lipid head-groups
-Alpha-helical membrane proteins are inserted into membranes in a variety of orientations
U1-8 Membrane-Associated Enzymes [Full Text] [PDF]
-The catalytic domains of most membrane-associated enzymes lie outside the lipid bilayer
-Membrane-anchored enzymes can be attached to the membrane in different ways
-Some enzymes have their catalytic domains inside the membrane bilayer
U1-9 Ion Channels: Potassium Ion Channels [Full Text] [PDF]
-Ion channels enable charged species to flow into and out of the cell across the hydrophobic lipid bilayer
-The opening of most potassium channels is rapid, selective and regulated
-Potassium channels contain a selectivity filter
-The opening and closing of ion channels is regulated in three different ways
U1-10 Pore-Forming Channel Proteins [Full Text] [PDF]
-Many neutral substances diffuse across membranes through pores
-Aquaporin pore size and polarity discriminate between water and protons
-Some pore-forming proteins are toxic to cells
U1-11 Active Transport: Major Facilitator Superfamily Transporters [Full Text] [PDF]
-Major facilitator superfamily transporters utilize ion gradients to move substrates across membranes
-MFS transporters share a common fold
-The glycerol-3-phosphate transporter uses ligand-induced conformational changes to move its substrates in opposite directions across the cell membrane
-Lactose permease transports lactose and protons together in the same direction
U1-14 Membrane Ca2+-ATPases: Overview [Full Text] [PDF]
-Intracellular calcium levels are mainly regulated by ATP-dependent calcium pumps
-The sarcoplasmic reticulum Ca2+-ATPase governs the calcium content of muscle cells
-The activity of Ca2+-ATPases is highly regulated
U1-15 Membrane Ca2+-ATPases: SERCA Structure and Function [Full Text] [PDF]
-The Ca2+-ATPase of the sarcoplasmic reticulum is the best understood ion pump
-The sarcoplasmic reticulum Ca2+-ATPase is a molecular machine driven by large conformational changes
Updates - 2005-2006
Chapter 2: From Structure to Function
Enzyme kinetics
U2-1 Enzyme Kinetics: General Principles [Full Text] [PDF]
-Reaction rates reflect key properties of enzymes and the reactions they catalyze
-Reaction rates depend on collisions between reacting species, which in turn depend on concentrations and temperature
-Reaction kinetics are described by rate constants
U2-2 Fundamental Kinetic Properties of Enzyme-Catalyzed Reactions [Full Text] [PDF]
-Vmax and Km are two key measurable properties of enzymes
-Enzyme-catalyzed reactions must involve formation of an enzyme–substrate complex, followed by one or more chemical steps
-Enzyme kinetic parameters can be determined by several analytical methods
U2-3 Analysis of Enzyme Reaction Rate Data [Full Text] [PDF]
-kcat/Km can be interpreted in terms of enzyme specificity and catalytic efficiency
-Enzyme-catalyzed reactions can have multiple steps with several intermediates
-The temperature dependence of enzyme reactions provides information about transition state energies
U2-4 Enzyme Regulation: Kinetic Consequences [Full Text] [PDF]
-Enzyme reactions can be slowed by the presence of inhibitors
-Enzyme reactions can be activated by the binding of extraneous ligands
Updates – 2004-2005
Chapter 1: From Sequence to Structure
Secondary structure
U1-1 Importance and Determinants of Secondary Structure [Full Text] [PDF]
-Folded proteins have segments of regular conformation
-The arrangement of secondary structure elements provides a convenient way of classifying types of folds
-Steric constraints dictate the possible types of secondary structure
-The simplest secondary structure element is the beta turn
U1-2 Prediction of Secondary Structure [Full Text] [PDF]
-Certain amino acids are more usually found in alpha helices, others in beta sheets
Protein folding
U1-3 Principles of Protein Folding [Full Text] [PDF]
-The folded structure of a protein is determined by its primary structure
-Competition between self-interactions and interactions with water drives protein folding
-Computational prediction of folding is not yet reliable
-Helical membrane proteins may fold by condensation of preformed secondary structure elements in the bilayer
U1-4 Chaperones and Protein Folding [Full Text] [PDF]
-The interior of the cell presents special obstacles to protein folding
-Chaperones assist folding of newly synthesized and misfolded proteins
U1-5 Protein Misfolding and Disease [Full Text] [PDF]
-The cell has several strategies for coping with misfolded proteins
-Depletion or accumulation of misfolded proteins can lead to many types of disease
Chapter 3: Control of Protein Function
Control by pH and redox
U3-1 Control by pH [Full Text] [PDF]
-Protein function is modulated by the pH of the environment in which the protein operates
-Changes in pH can drastically alter protein structure and function
U3-2 Redox Control [Full Text] [PDF]
-Changes in redox environment can greatly affect protein structure and function
-Cells have specific mechanisms to control their internal redox environment
-Redox-dependent protein modifications can regulate biological activity
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