PROSITE documentation PDOC51145
ZU5 domain profile


The ZU5 domain is a domain of ~150 residues present in zona occludens 1 (ZO-1) protein, in unc5-like netrin receptors and in ankyrins. The ZU5 domain is named after the mouse tight junction protein ZO-1 and the C. elegans uncoordinated protein 5 (unc-5) and related Unc5-like netrin receptors. ZU5 domains are found in eukaryotic proteins that in most cases contain a C-terminal death domain (see <PDOC50017>). Other domains which can be found N-terminal to a ZU5 domain are ankyrin repeats (see <PDOC50088>); Ig-like (see <PDOC50835>) and TSP1 repeats (see <PDOC50092>); PDZ (see <PDOC50106>), SH3 (see <PDOC50002>) and guanylate kinase (see <PDOC00670>); or leucine-rich repeats (LRR) [1,2,3,4]. The ZU5 domain is a versatile protein-protein interaction module with more than one interaction surface that acts in different modes to interact with a variety of partners [6].

The ZU5 domain is formed by a compact β-sheet-rich core with a variable number of surface loops and helices (see <PDB:3UD1>). The β-strand-rich core is made of two antiparallel sheets interacting with each other in parallel to form a β-sandwich [6,7].

Some proteins known to contain a ZU5 domain:

  • Mammalian zona occludens 1 (ZO-1) or tight junction ZO1 protein, implicated in junction formation. ZO-1 belongs to the membrane-associated guanylate kinase (MAGUK) proteins (see <PDOC00670>).
  • Caenorhabditis elegans unc-5, a receptor for netrin (unc-6) required for axon repulsion.
  • Vertebrate Unc5 homologues (UNC5H1-4), which are axon guidance receptors that mediate netrin-1-dependent chemorepulsion, and are receptors that mediate netrin-1-independent apoptosis.
  • Mammalian ankyrins 1-3, which attach the cytoskeleton to the plasma membrane and organize diverse membrane-spanning proteins, such as ion channels and transporters.
  • Caenorhabditis elegans unc-44, an ankyrin-like protein involved in axon guidance.
  • Mammalian PIDD (p53-induced protein with a death domain) or LRDD (leucine rich repeat and death domain containing protein), a regulator of apoptosis in response to genotoxic stimuli [4]. PIDD contains two ZU5 domains.
  • Vertebrate SH3 domain-binding protein 4 (Sh3bp4), may act as a negative regulator of the amino acid-induced TOR signaling by inhibiting the formation of active Rag GTPase complexes.
  • Mammalian metastasis-associated in colon cancer protein 1 (MACC1), acts as a transcription activator for MET and as a key regulator of HGF-MET signaling.
  • Vertebrate Death domain-containing protein 1 (DTHD1), contains two ZU5 domains.

The profile we developed covers the entire ZU5 domain.


The ZU5 domain is also known as ZU-5 domain.

Last update:

February 2017 / Profile and text revised.


Technical section

PROSITE method (with tools and information) covered by this documentation:

ZU5, PS51145; ZU5 domain profile  (MATRIX)


1AuthorsLeonardo E.D. Hinck L. Masu M. Keino-Masu K. Ackerman S.L. Tessier-Lavigne M.
TitleVertebrate homologues of C. elegans UNC-5 are candidate netrin receptors.
SourceNature 386:833-838(1997).
PubMed ID9126742

2AuthorsAckerman S.L. Kozak L.P. Przyborski S.A. Rund L.A. Boyer B.B. Knowles B.B.
TitleThe mouse rostral cerebellar malformation gene encodes an UNC-5-like protein.
SourceNature 386:838-842(1997).
PubMed ID9126743

3AuthorsZhang J. Xu L.G. Han K.J. Shu H.B.
TitleIdentification of a ZU5 and death domain-containing inhibitor of NF-kappaB.
SourceJ. Biol. Chem. 279:17819-17825(2004).
PubMed ID14769797

4AuthorsTinel A. Tschopp J.
TitleThe PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress.
SourceScience 304:843-846(2004).
PubMed ID15073321

5AuthorsMohler P.J. Yoon W. Bennett V.
TitleAnkyrin-B targets beta2-spectrin to an intracellular compartment in neonatal cardiomyocytes.
SourceJ. Biol. Chem. 279:40185-40193(2004).
PubMed ID15262991

6AuthorsYasunaga M. Ipsaro J.J. Mondragon A.
TitleStructurally similar but functionally diverse ZU5 domains in human erythrocyte ankyrin.
SourceJ. Mol. Biol. 417:336-350(2012).
PubMed ID22310050

7AuthorsWang C. Yu C. Ye F. Wei Z. Zhang M.
TitleStructure of the ZU5-ZU5-UPA-DD tandem of ankyrin-B reveals interaction surfaces necessary for ankyrin function.
SourceProc. Natl. Acad. Sci. U.S.A. 109:4822-4827(2012).
PubMed ID22411828

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