Full length TECPR1 displays 'cis' Dysferlin domain architecture

Area of Science:

• Cellular Biology
• Molecular Biology
• Structural Biology

Background:

• Tectonin Beta-Propeller Repeat containing 1 (TECPR1) is crucial for the noncanonical autophagy pathway, Sphingomyelin TECPR1 induced LC3 lipidation (STIL).
• TECPR1 functions as an E3-like ligase, identifying sphingomyelin on damaged cellular membranes.
• The structural underpinnings of TECPR1's function remained largely unknown despite its known domains.

Purpose of the Study:

• To determine the full-length structure of TECPR1.
• To elucidate the structural basis of TECPR1's membrane-binding mechanism.
• To provide a structural framework for understanding TECPR1's role in STIL autophagy.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to resolve the structure of full-length TECPR1.
• Molecular dynamics (MD) simulations were employed to assess TECPR1's structural stability during membrane association.

Main Results:

• The first high-resolution cryo-EM structure of TECPR1 revealed an elongated, hook-shaped architecture.
• Dysferlin domains are arranged in a cis configuration, stabilized by an uncharacterized intramolecular interface between tectonin repeat 1 and PH domains.
• MD simulations confirmed TECPR1's structural integrity upon membrane binding, highlighting the importance of domain arrangement.

Conclusions:

• The determined TECPR1 structure provides a foundational understanding of its domain organization and membrane interaction.
• This structural framework explains how TECPR1's architecture facilitates its function in the STIL autophagy pathway.
• The findings offer insights into the regulation of noncanonical autophagy by TECPR1.