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Phospholipid transfer function of PTPIP51 at mitochondria-associated ER membranes

Hyun Ku Yeo1, Tae Hyun Park1,2, Hee Yeon Kim1

  • 1Research Institute, National Cancer Center, Goyang-si, Korea.

EMBO Reports
|May 3, 2021
PubMed

Insights

Researchers identified PTPIP51 as a key protein facilitating phospholipid transfer at mitochondria-associated ER membranes (MAMs). This discovery sheds light on crucial cellular lipid transport and mitochondrial-ER connections.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Structural Biology

Background:

  • Mitochondria and endoplasmic reticulum (ER) interact at mitochondria-associated ER membranes (MAMs) for cellular functions.
  • Phospholipid and Ca2+ transfer at MAMs are vital, but human protein complexes involved remain largely unknown.
  • PTPIP51 is a mitochondrial protein known to interact with the ER protein VAPB at MAMs.

Purpose of the Study:

  • To elucidate the structural and functional role of PTPIP51 in phospholipid transfer at MAMs.
  • To identify the protein complexes responsible for phospholipid transfer at MAMs in human cells.
  • To characterize the interaction between PTPIP51 and VAPB.

Main Methods:

  • Determined the crystal structure of the PTPIP51 tetratricopeptide repeat (TPR) domain.
  • Investigated PTPIP51's in vitro phospholipid binding and transfer capabilities, focusing on phosphatidic acid.
  • Assessed the impact of PTPIP51 depletion on cellular cardiolipin levels.
  • Confirmed the interaction interface between PTPIP51 and VAPB using structural and biochemical approaches.

Main Results:

  • The crystal structure of PTPIP51_TPR revealed a canonical TPR fold with an associated lipid-like molecule.
  • PTPIP51 demonstrated in vitro binding and transfer activity for phospholipids, notably phosphatidic acid.
  • Cellular PTPIP51 depletion led to reduced mitochondrial cardiolipin levels.
  • The PTPIP51-VAPB interaction is mediated by PTPIP51's FFAT-like motif and VAPB's MSP domain.

Conclusions:

  • PTPIP51 functions as a phospholipid transfer protein.
  • PTPIP51 plays a role in maintaining mitochondrial cardiolipin levels.
  • PTPIP51 contributes to tethering mitochondria to the ER via its interaction with VAPB at MAMs.
Keywords:
MAMPTPIP51endoplasmic reticulummitochondriaphospholipid

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