Protrudin binds atlastins and endoplasmic reticulum-shaping proteins and regulates network formation

Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):14954-9. doi: 10.1073/pnas.1307391110. Epub 2013 Aug 22.


Hereditary spastic paraplegias are inherited neurological disorders characterized by progressive lower-limb spasticity and weakness. Although more than 50 genetic loci are known [spastic gait (SPG)1 to -57], over half of hereditary spastic paraplegia cases are caused by pathogenic mutations in four genes encoding proteins that function in tubular endoplasmic reticulum (ER) network formation: atlastin-1 (SPG3A), spastin (SPG4), reticulon 2 (SPG12), and receptor expression-enhancing protein 1 (SPG31). Here, we show that the SPG33 protein protrudin contains hydrophobic, intramembrane hairpin domains, interacts with tubular ER proteins, and functions in ER morphogenesis by regulating the sheet-to-tubule balance and possibly the density of tubule interconnections. Protrudin also interacts with KIF5 and harbors a Rab-binding domain, a noncanonical FYVE (Fab-1, YGL023, Vps27, and EEA1) domain, and a two phenylalanines in an acidic tract (FFAT) domain and, thus, may also function in the distribution of ER tubules via ER contacts with the plasma membrane or other organelles.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / ultrastructure
  • GTP-Binding Proteins / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Membrane Proteins / metabolism*
  • Membrane Transport Proteins / metabolism
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Spastic Paraplegia, Hereditary / genetics
  • Spastic Paraplegia, Hereditary / metabolism
  • Spastin
  • Vesicular Transport Proteins / chemistry
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*


  • Membrane Proteins
  • Membrane Transport Proteins
  • Mutant Proteins
  • Recombinant Proteins
  • Vesicular Transport Proteins
  • ZFYVE27 protein, human
  • ATL1 protein, human
  • Adenosine Triphosphatases
  • GTP-Binding Proteins
  • Spastin
  • SPAST protein, human