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2.A.6.9.2
Protein dispatched homologue 1 (Dispatched-1, DispA, DISP1) of 1521 aas and 12 TMSs.  The human ortholog (Q96F81, 1524 aas) is 83% identical.  They play roles in congenital diaphragmatic hernia (CDH) and associated pulmonary hypoplasia (PH) in humans and mice (Takahashi et al. 2018). Hedgehog (HH) signaling is essential for metazoan development. The HH ligand is secreted into the extracellular space by DISP1. Chen et al. 2020 reported the cryo-EM structure of human DISP1. It contains 12 TMSs and two extracellular domains (ECDs) like other RND homologs. Its ECDs reveal an open state, in contrast to its structural homologues PTCH1 and NPC1, whose extracellular/luminal domains adopt a closed state. The low-resolution structure of the DISP1 complex with dual lipid-modified HH ligand reveals how the ECDs of DISP1 engage with HH ligand. Several cholesterol-like molecules were found in the TMSs, implying a transport-like function of DISP1 (Chen et al. 2020). Dispatched enables tissue-patterning activity of the lipid-modified Hedgehog protein by releasing it from tightly -localized sites of embryonic expression. Wang et al. 2021 determined a cryoEM structure of the mouse DISP1, revealing three Na+ ions coordinated within a channel that traverses its transmembrane domain. The rate of Hedgehog export is dependent on the Na+ gradient across the plasma membrane. The transmembrane channel and Na+ binding are disrupted in DISP1-NNN, a variant with asparagine substitutions for three intramembrane aspartate residues that each coordinate and neutralize the charge of one of the three Na+ ions. DISP1-NNN and variants that disrupt single Na+ sites retain binding to, but are impaired in export of the lipid-modified Hedgehog protein to the SCUBE2 acceptor. Interaction of the amino-terminal signalling domain of the Sonic hedgehog protein (ShhN) with DISP1 occurs via an extensive buried surface area and contacts with an extended furin-cleaved DISP1 arm. Variability analysis reveals that ShhN binding is restricted to one extreme of a continuous series of DISP1 conformations. The bound and unbound DISP1 conformations display distinct Na+-site occupancies, which suggests a mechanism by which transmembrane Na+ flux may power extraction of the lipid-linked Hedgehog signal from the membrane. Na+-coordinating residues in DISP1 are conserved in PTCH1 and other metazoan RND family members, suggesting that Na+ flux powers their conformationally driven activities (Wang et al. 2021). The substrate is probably the sonic hedgehog (SHH) protein of 462 aas and one N-terminal TMS.

Accession Number:Q3TDN0
Protein Name:Protein dispatched homologue 1
Length:1521
Molecular Weight:170130.00
Species:Mus musculus (Mouse) [10090]
Number of TMSs:12
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate sodium(1+), protein polypeptide chain

Cross database links:

Entrez Gene ID: 68897   
Pfam: PF03176    PF02460   
KEGG: mmu:68897   

Gene Ontology

GO:0016021 C:integral to membrane
GO:0008158 F:hedgehog receptor activity
GO:0015197 F:peptide transporter activity
GO:0007368 P:determination of left/right symmetry
GO:0060539 P:diaphragm development
GO:0009953 P:dorsal/ventral pattern formation
GO:0009880 P:embryonic pattern specification
GO:0007225 P:patched ligand maturation
GO:0007224 P:smoothened signaling pathway

References (5)

[1] “Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched.”  Ma Y.et.al.   12372301
[2] “Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling.”  Kawakami T.et.al.   12421714
[3] “The transcriptional landscape of the mammalian genome.”  Carninci P.et.al.   16141072
[4] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[5] “Mouse Dispatched homolog1 is required for long-range, but not juxtacrine, Hh signaling.”  Caspary T.et.al.   12372258

External Searches:

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MAVISGSDSV LLSNGSISTS TSNPSPLSPS DGDLPAQHLG PRETPRTKAS PNGCLQLNGT 
61:	VKSSFLPLDN QRTPQTPTQC CHPCPYHHPV SSHSNHQECH PEAGLAASPA LASCRMQPHS 
121:	EYSASLCPNH SPVYQAAHCL QPSPSFCLHH PWPDHFQHQP VRQHLTIIRP SRPFKFPRSY 
181:	AALLADWPVV VLGMCTLLIV VCALVGVLVP ELPDFSDPLL GFEPRGTTIG QRLVTWNNMM 
241:	RNTGYKATLA NYPYKYAEEQ ARSHRDDRWS DDHHERERRE VDWNFQKDSF FCDVPSDGYS 
301:	RVVFASAGGE TLWNLPAIKS MCDVDNSRIR SHPQFSDLCQ RTTAVSCCPS WTLGNYIAIL 
361:	NNRSSCQKIV ERDVSHTLKL LRTCAKHYQN GTLGPDCWDK AARRKDQLKC TNVPRKCTKY 
421:	NAVYQILHYL VDKDFMTPKT ADYAVPALKY SMLFSPTEKG ESMMNIYLDN FENWNSSDGI 
481:	TTVTGIEFGI KHSLFQDYLL MDTVYPAIAI AIVLLIMCVY TKSMFITLMT MFAIISSLIV 
541:	SYFLYRVVFN FEFFPFMNLT ALIILVGIGA DDAFVLCDVW NYTKFDKPRA ETSEAVSVTL 
601:	QHAALSMFVT SFTTAAAFYA NYVSNITAIR CFGVYAGTAI LVNYVLMVTW LPAVIVLHER 
661:	YLLNIFTCFR KPQPQAYDKS CWAVLCQKCR RVLFAVSEAS RIFFEKVLPC IVIKFRYLWL 
721:	IWFLALTVGG AYIVCVNPKM KLPSLELSEF QVFRSSHPFE RYDAEFKKLF MFERVHHGEE 
781:	LHMPITVIWG VSPEDSGDPL NPKSKGELTL DSTFNIASPA SQAWILHFCQ KLRNQTFFHQ 
841:	TEQQDFTSCF IETFKQWMEN QDCDEPALYP CCSHCSFPYK QEVFELCIKK AIMELDRSTG 
901:	YHLNNKTPGP RFDINDTIRA VVLEFQSTFL FTLAYEKMQQ FYKEVDSWIS HELSSAPEGL 
961:	SRGWFVSNLE FYDLQDSLSD GTLIAMGLSV AVAFSVMLLT TWNIIISLYA IVSIAGTIFV 
1021:	TVGSLVLLGW ELNVLESVTI SVAVGLSVDF AVHYGVAYRL APDPDREGKV IFSLSRMGSA 
1081:	IAMAALTTFV AGAMMMPSTV LAYTQLGTFM MLVMCVSWAF ATFFFQCLCR CLGPQGTCGQ 
1141:	IPFPTKLQCS PFSHTLSARP GDRGPSKTHA ASAYSVDARG QKSQLEHEFY ELQPLASHSC 
1201:	TSSEKTTYEE PHTCSEFFNG QAKNLRMPVP AAYSSELTKS PSSEPGSALL QSCLEQDTVC 
1261:	HFSLNPRCNC RDAYTHLQYG LPEIHCQQMG DSLCHKCAST AGGFVQIQSS VAPLKASHQA 
1321:	AEGLLHPAQH MLPPGMQNSR PRNFFLHSVQ HFQAQENLGR TSTHSTDERL PRTAELSPPP 
1381:	SDSRSTESFQ RACCHPENNQ RRLCKSRDPG DTEGSGGTKS KVSGLPNQTD KEEKQVEPSL 
1441:	LQTDETVNSE HLNHNESNFT FSHLPGEAGC RSCPNSPQSC RSIMRSKCGT EDCQTPNLEA 
1501:	NVPAVPTHSD LSGESLLIKT L