JW

Protein Interactions and Allostery — Study Notes

Protein Interactions: Noncovalent Bonds

  • Objectives (from end of video): Explain how proteins interact using non-covalent bonds; Define and explain allostery.
  • Proteins will often bind together to regulate or create functions. (Page 3)
  • Proteins interact together, typically using non-covalent (flexible!) interactions.
    • Noncovalent bonds enable reversible, dynamic interactions between proteins and ligands or between proteins themselves. (Page 4)
  • When proteins bind together, the number of types of interactions will determine the strength (duration) of the interaction. (Page 5)
  • The tertiary structure of a protein can create binding sites that “fit” other molecules to form many non-covalent interactions. (Page 6)
  • Some proteins have multiple binding sites, which allow for regulation. (Page 7)
  • Example: Enzymes often have an active site for the substrate and an allosteric site for regulation. (Page 8)
  • The most important concept of this semester is: ALLOSTERY. (Page 9)

Induced fit and allostery: how binding changes shape

  • When two molecules interact, their shapes change slightly to form interactions with the new molecule. This adjustment is known as “induced fit.” (Page 10)
    • Induced fit denotes conformational adjustment of a protein upon ligand binding, enabling more favorable interactions.
  • Allostery — molecules have multiple stable conformations, which are determined by their binding partners. (Page 11)
  • We will see allostery nearly every day. A classic example is a G-protein coupled receptor (GPCR) binding to a G-protein, which causes an allosteric change in the G-protein to allow the exchange of a nucleotide and activate the G-protein for its next function. (Page 12)
  • This example and description are drawn from Hardin, World of the Cell, 9th edition; reference also: Alberts, ECB, 5th edition, Chapter 4.
  • Slide note: The most important concept of this semester is: ALLOSTERY. You can analyze an allosteric change by asking: 1) what interaction led to this change? 2) what is the consequence of this interaction? (Page 13)

Binding sites, regulation, and enzyme allostery

  • The tertiary structure of a protein can create binding sites that fit other molecules to form many non-covalent interactions. This enables regulation and the formation of functional complexes. (Page 6)
  • Some proteins have multiple binding sites, which allow for regulation. (Page 7)
  • Enzymes often have:
    • an active site for the substrate, and
    • an allosteric site for regulation. (Page 8)

Allostery: definitions, mechanisms, and implications

  • Allostery is the phenomenon where molecules have multiple stable conformations dictated by binding partners. This allows regulation of activity at sites distant from the binding site. (Page 11)
  • Induced fit is the conformational adjustment that occurs when a ligand binds, enabling the interaction to become more favorable. (Page 10)
  • Allosteric changes propagate through the protein structure to alter function, often converting an inactive state to an active state or vice versa.
  • Allostery is observed across daily biochemical processes and is a central theme in signaling and regulation. (Page 12)

GPCR-G protein example (illustrative case)

  • Example described: A G-protein coupled receptor binds to a G-protein, causing an allosteric change in the G-protein that allows nucleotide exchange and activation of the G-protein for its next function.
  • Mechanism outline:
    • GPCR binding induces a conformational change in the G-protein.
    • This conformational change facilitates nucleotide exchange: the bound GDP is released and replaced by GTP.
    • The G-protein becomes activated and can propagate the signal to downstream effectors.
  • Notation (illustrative):
    \mathrm{G\text{-}protein\text{-}GDP} \xrightarrow{\text{GPCR binding}} \mathrm{G\text{-}protein\text{-}GTP} \rightarrow \text{activation}
  • Source references: Alberts, ECB, 5th edition, Chapter 4; Hardin, World of the Cell, 9th edition; specific example described in page 12.

Practical perspective and study questions

  • Allostery is a central, frequently encountered concept; expect it to appear in various contexts and systems.
  • Analytical questions to guide understanding:
    1) What interaction led to the conformational change?
    2) What is the consequence of this interaction?

Summary of key concepts

  • Proteins interact via noncovalent bonds, enabling flexible and reversible associations.
  • The strength/duration of protein interactions depend on the number and variety of noncovalent interactions.
  • The tertiary structure creates binding sites that can accommodate ligands/substrates to form multiple noncovalent interactions.
  • Some proteins have multiple binding sites and can be regulated through allostery.
  • Enzymes often feature an active site and an allosteric site, allowing regulation of catalytic activity.
  • Induced fit describes the shape change upon binding that stabilizes the interaction.
  • Allostery involves multiple stable conformations of a molecule, driven by the binding partners, and is a pervasive mechanism in signaling and regulation.
  • GPCR-G protein interactions provide a concrete example of allosteric changes enabling nucleotide exchange and downstream activation.