Transferrin receptor internalization sequence YXRF implicates a tight turn as the structural recognition motif for...

Area of Science:

• Molecular and Cell Biology
• Biochemistry
• Structural Biology

Background:

• Cellular endocytosis is a fundamental process for nutrient uptake and receptor regulation.
• Internalization sequences on receptors mediate their entry into cells via endocytosis.
• The transferrin receptor (TR) is a key protein involved in iron uptake.

Purpose of the Study:

• To identify the specific internalization sequence of the human transferrin receptor (TR).
• To investigate the structural and conformational requirements for TR internalization.
• To compare the structural basis of internalization motifs between different receptors.

Main Methods:

• Functional studies were performed on 24 human transferrin receptor mutants.
• An unbiased search of protein structural databases was conducted to find YXRF analogs.
• Structural analysis focused on identifying favored conformations, such as tight turns.

Main Results:

• The tetrapeptide sequence YXRF was identified as the internalization sequence for TR.
• Internalization activity was independent of YXRF position within the cytoplasmic domain (if >7 residues from transmembrane region).
• YXRF analogs and related motifs (e.g., NPXY) showed a preference for exposed tight-turn conformations.

Conclusions:

• The YXRF sequence is a critical determinant for transferrin receptor endocytosis.
• A common structural chemistry, specifically an exposed tight turn, underlies distinct receptor internalization motifs.
• This structural motif is implicated as the recognition element for high-efficiency endocytosis.