Selective integrin endocytosis is driven by interactions between the integrin α-chain and AP2

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Integrins are crucial cell-surface adhesion molecules involved in various cellular functions.
• Integrin internalization occurs via clathrin-mediated endocytosis (CME), but selective endocytosis was not understood.

Purpose of the Study:

• To investigate whether specific integrin heterodimers can be selectively endocytosed.
• To identify the molecular mechanisms governing selective integrin internalization.

Main Methods:

• Structural determination of the integrin α4-tail motif complexed with AP2 C-micro2 subunit.
• Isothermal titration calorimetry to confirm molecular interactions.
• Mutagenesis studies to assess the functional impact of the YxxΦ motif.

Main Results:

• A subset of α subunits possess a conserved YxxΦ motif enabling selective internalization by the AP2 endocytic adaptor.
• The structure of the α4-tail motif-AP2 complex was elucidated, confirming their interaction.
• Mutating the YxxΦ motif disrupted selective integrin endocytosis and reduced integrin-mediated cell migration.

Conclusions:

• Integrins possess a selective internalization mechanism mediated by α subunit YxxΦ motifs and AP2.
• This pathway allows for regulated integrin turnover, adapting to changing extracellular matrix conditions.
• The findings provide insights into the dynamic regulation of cell adhesion and migration.