AP Syllabus focus:
‘Mutations in receptor proteins can disrupt signal binding or transduction, leading to abnormal cellular responses and phenotypes.’
Receptors convert external information into specific cellular responses. When receptor genes mutate, signaling can become weaker, stronger, mistimed, or misrouted, changing cell behavior and producing abnormal phenotypes across tissues.
How receptor mutations alter signaling
Receptors are proteins whose structure determines how they bind a signal (ligand) and how they transduce that information to intracellular components.
G-protein signaling depends on receptor-driven nucleotide exchange (GDP to GTP) on the Gα subunit, which turns the pathway “on” and allows downstream effectors to be activated. Termination occurs when GTP is hydrolyzed back to GDP, emphasizing how mutations that alter activation or shutoff can change signaling duration and cellular response intensity. Source
Mutations can affect:
Ligand recognition (whether binding occurs)
Signal relay (whether binding triggers the proper conformational change)
Signal strength and duration (how much pathway activation occurs and for how long)
Cellular location (whether the receptor reaches the correct membrane/compartment)
Core idea: structure–function disruption
Because binding and activation depend on precise 3D shape, even a single amino acid substitution can:
Change receptor folding and stability
Alter charge/hydrophobicity at binding or activation interfaces
Disrupt interaction sites for adaptor proteins, G proteins, or kinases
Mutations that disrupt ligand binding (reception failures)
Many receptors have an extracellular ligand-binding domain; mutations here often reduce or abolish binding.
Reduced affinity: ligand binds weakly, requiring higher ligand concentration for response
No binding: receptor cannot recognize ligand, producing a functional “silence” to that signal
Altered specificity: receptor binds the wrong ligand(s) or responds inappropriately to similar molecules
A binding-defective receptor commonly causes loss of pathway activation, which can change downstream gene expression and cellular activity, producing an abnormal phenotype.
Mutations that disrupt signal transduction (activation/relay failures)
Some mutations allow ligand binding but prevent the receptor from initiating the intracellular response. Common mechanisms include:
Ligand binding can trigger receptor dimerization, bringing intracellular kinase domains close enough to phosphorylate one another (autophosphorylation). This phosphorylation creates docking sites and initiates downstream signaling, illustrating why mutations that block dimerization or kinase function can prevent signal relay even when ligand binding still occurs. Source
No activation conformational change after ligand binding
Defective dimerization or clustering (important for many receptors that must pair up to signal)
Broken intracellular docking sites for signaling proteins
Impaired enzymatic activity (for receptors that act as enzymes or recruit enzymes)
These mutations can yield a receptor that “hears” the signal but cannot “speak” to the cell interior, leading to weak or absent cellular responses.
Loss-of-function vs gain-of-function outcomes
Some receptor mutations reduce signaling; others increase it or make it independent of ligand presence.
Gain-of-function mutation: A genetic change that increases protein activity, causes constitutive (ligand-independent) activity, or produces a new/expanded function.
Gain-of-function receptor mutations may cause:
Constitutive activation: receptor signals without ligand, driving continuous pathway activity
Hypersensitivity: normal ligand levels trigger exaggerated responses
Prolonged signaling: receptor fails to turn off, extending transcriptional or metabolic changes
In contrast, loss-of-function receptor mutations typically cause:
Reduced sensitivity or complete unresponsiveness to a ligand
Failure to initiate essential cellular programs (e.g., differentiation, movement, secretion), depending on the pathway
Dominant-negative effects and receptor complexes
Many receptors function as multi-subunit complexes or require pairing.
Ligand binding can promote dimer formation, a common prerequisite for activation in receptors such as receptor tyrosine kinases. Because signaling depends on correct pairing and alignment of domains, a mutation that disrupts dimerization (or produces a defective partner) can reduce pathway activation even when ligand is present. Source
A mutant receptor can interfere with the normal receptor’s function.
Dominant-negative mutation: mutant receptor forms nonfunctional complexes with normal receptors, reducing overall signaling even when one normal allele is present
This can be especially impactful when receptors must dimerize; a defective partner can block activation of the entire complex
Mislocalisation and trafficking defects
Even a perfectly functional binding/activation site is useless if the receptor is not in the right place. Mutations can disrupt:
Signal peptide or membrane-targeting sequences (receptor never reaches the plasma membrane)
Proper folding in the ER, leading to degradation instead of delivery
Membrane anchoring, causing receptors to be absent from the cell surface
Consequences include reduced receptor density at the membrane, lowering the probability of ligand binding and decreasing pathway activation.
Abnormal regulation: desensitisation and signal termination defects
Cells regulate receptor signaling to prevent overstimulation. Mutations can disrupt shutoff mechanisms:
Failure of receptor inactivation after signaling
Defective internalisation (receptor remains active at the surface longer than normal)
Impaired interaction with regulatory proteins that normally dampen signaling
Alternatively, a receptor may desensitise too easily:
Rapid inactivation after minimal stimulation, producing an under-response to persistent ligand
Effects on cellular responses and phenotypes
Receptor mutations ultimately alter cellular behavior by changing downstream pathway outputs, such as:
Gene expression patterns (turning genes on/off incorrectly)
Enzyme activity and metabolic regulation
Cytoskeletal changes affecting shape, adhesion, or migration
Cell-cycle entry or survival decisions, depending on what the pathway controls
Because different tissues express different receptors and downstream components, the same type of mutation (e.g., loss of binding) can produce distinct phenotypes in different cell types, but the unifying theme is altered response to an external signal.
FAQ
It can improve shape complementarity or strengthen noncovalent interactions at the binding site (e.g., additional hydrogen bonds or better charge pairing).
Increased affinity can shift the dose–response curve so lower ligand concentrations trigger signalling.
If receptors must form dimers/complexes, a mutant subunit can poison the complex (dominant-negative effect).
This reduces the number of functional receptors below what one normal allele would otherwise produce.
Common approaches include:
Ligand-binding assays (labelled ligand; quantify binding)
Measuring downstream pathway readouts (e.g., phosphorylation status, reporter gene activity)
A binding-normal but response-negative pattern suggests a transduction defect.
Yes. Distinct defects (no surface expression vs no ligand binding vs no activation) can all reduce pathway output below a threshold needed for normal function.
Phenotypes often reflect pathway output level, not the precise molecular defect.
Tissue specificity can result from:
Where the receptor is expressed
Availability of downstream signalling proteins
Differences in feedback regulators
Thus, constitutive signalling can have strong effects only in cells wired to respond to that pathway.
Practice Questions
Describe two different ways a mutation in a receptor protein could alter a cell’s response to a signalling molecule. (2 marks)
Any one valid mechanism affecting ligand binding (e.g., reduced affinity/no binding/altered specificity) (1)
Any one valid mechanism affecting transduction/regulation (e.g., cannot activate after binding/constitutive activation/defective internalisation or trafficking) (1)
A receptor normally activates a signalling pathway only when its ligand binds. Explain how receptor mutations could lead to (i) no response even when ligand is present and (ii) signalling when ligand is absent, and link each to an abnormal phenotype. (5 marks)
(i) No response with ligand present: mutation reduces/abolishes ligand binding OR binds but cannot undergo activation conformational change (1)
Additional detail for (i): defective intracellular docking/enzymatic activity/dimerisation prevents downstream activation (1)
(ii) Signalling without ligand: gain-of-function/constitutive activation due to receptor being locked in “active” conformation (1)
Additional detail for (ii): failure of shutoff (e.g., impaired inactivation/internalisation) prolongs signalling (1)
Links altered signalling to abnormal phenotype via changed gene expression/cell behaviour (e.g., inappropriate proliferation, secretion, migration, differentiation) (1)
