VHP

Villin headpiece domain

• SMART accession number: SM00153
• Description: -
• Interpro abstract (IPR003128):

  Villin is an F-actin bundling protein involved in the maintenance of the microvilli of the absorptive epithelia. The villin-type "headpiece" domain is a modular motif found at the extreme C terminus of larger "core" domains in over 25 cytoskeletal proteins in plants and animals, often in assocation with the Gelsolin repeat. Although the headpiece is classified as an F-actin-binding domain, it has been shown that not all headpiece domains are intrinsically F-actin-binding motifs, surface charge distribution may be an important element for F-actin recognition [ (PUBMED:11977079) ]. An autonomously folding, 35 residue, thermostable subdomain (HP36) of the full-length 76 amino acid residue villin headpiece, is the smallest known example of a cooperatively folded domain of a naturally occurring protein. The structure of HP36, as determined by NMR spectroscopy, consists of three short helices surrounding a tightly packed hydrophobic core [ (PUBMED:12095260) ].

• GO process: cytoskeleton organization (GO:0007010)
• GO function: actin binding (GO:0003779)

There are 6527 VHP domains in 6527 proteins in SMART's nrdb database.

Cellular role (predicted cellular role)

Binding / catalysis: actin-binding

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Lundquist EA, Herman RK, Shaw JE, Bargmann CI
• UNC-115, a conserved protein with predicted LIM and actin-binding domains, mediates axon guidance in C. elegans.
• Neuron. 1998; 21: 385-92

Axon guidance receptors modulate the growth cone cytoskeleton through signaling pathways that are not well understood. Here, we describe the C. elegans unc-115 gene, which encodes a candidate cytoskeletal linker protein that acts in axon guidance. unc-115 mutants have defects in a subset of axons, particularly as the affected axons change environments during outgrowth. The unc-115 gene encodes a putative actin-binding protein that is similar to the human actin-binding protein abLIM/limatin; it has a villin headpiece domain and three LIM domains that could mediate protein interactions. unc-115 is expressed in neurons during their development and is required cell-autonomously in certain neurons for normal axon guidance. We propose that UNC-115 modulates the growth cone actin cytoskeleton in response to signals received by growth cone receptors.

• McKnight CJ, Matsudaira PT, Kim PS
• NMR structure of the 35-residue villin headpiece subdomain.
• Nat Struct Biol. 1997; 4: 180-4

The NMR structure of an autonomously folding subdomain from villin headpiece is reported. It forms a novel three helix structure with the actin-binding residues arrayed on the C-terminal helix.

• Doering DS, Matsudaira P
• Cysteine scanning mutagenesis at 40 of 76 positions in villin headpiece maps the F-actin binding site and structural features of the domain.
• Biochemistry. 1996; 35: 12677-85

Villin headpiece, the 76 amino acid, C-terminal domain of villin, is one of the two F-actin binding sites in villin necessary for F-actin bundling activity. Expression and study of recombinant headpiece revealed the domain to be remarkably thermostable (Tm = 74 degrees C) for a non-disulfide-bonded domain. Forty independent point mutations to cysteine of headpiece have been purified and tested for their actin binding activity, cysteine reactivity, and thermal stability. These assays identify two segments of headpiece, near amino acids 38 and 70 of headpiece, in which mutations to cysteine significantly disrupt cosedimentation of headpiece with F-actin. Assay of the thermal stability of these mutants and assay of the reactivity of the introduced cysteine show that these amino acids are mutations at the protein surface that do not perturb the overall structure of the domain. The actin binding mutants are replacements to cysteine of Lys38, Glu39, Lys65, Lys70, Lys71, Leu75, and Phe76 of headpiece. We propose that these discontinuous segments of charged amino acids define the F-actin binding contacts of the headpiece domain. The assay of mutants for effects on the thermal stability of helical structure as well as the assay of reactivity of the introduced sulfhydryl group identify candidate positions that are involved in the stabilizing core and internal structure of the domain. The cysteine scanning mutagenesis also identifies an amino-terminal subdomain (Val1-Leu35) and a predominantly helical carboxy-terminal subdomain (Pro36-Phe76).

• Rana AP, Ruff P, Maalouf GJ, Speicher DW, Chishti AH
• Cloning of human erythroid dematin reveals another member of the villin family.
• Proc Natl Acad Sci U S A. 1993; 90: 6651-5

Dematin is an actin-bundling protein originally identified in the human erythroid membrane skeleton. Its actin-bundling activity is abolished upon phosphorylation by the cAMP-dependent protein kinase and is restored after dephosphorylation. Here we report the complete primary structure of human erythroid dematin, whose sequence includes a homologue of the "headpiece" sequence found at the C terminus of villin. This headpiece is essential for villin function in inducing microvillar development and actin redistribution. The widespread expression of dematin transcripts in human tissues suggests that dematin and its homologues may substitute for villin in villin-negative tissues to regulate actin reorganization by a phosphorylation-regulated mechanism.

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
94.74	map04360	Axon guidance
5.26	map04810	Regulation of actin cytoskeleton

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with VHP domain which could be assigned to a KEGG orthologous group, and not all proteins containing VHP domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of VHP domains in PDB

PDB code	Title
1qqv	SOLUTION STRUCTURE OF THE HEADPIECE DOMAIN OF CHICKEN VILLIN
1qzp	NMR structure of the human dematin headpiece domain
1ujs	Solution structure of the Villin headpiece domain of human actin-binding LIM protein homologue (KIAA0843 protein)
1unc	Solution structure of the human villin C-terminal headpiece subdomain
1und	Solution structure of the human advillin C-terminal headpiece subdomain
1vii	THERMOSTABLE SUBDOMAIN FROM CHICKEN VILLIN HEADPIECE, NMR, MINIMIZED AVERAGE STRUCTURE
1wy3	Chicken villin subdomain HP-35, K65(NLE), N68H, pH7.0
1wy4	Chicken villin subdomain HP-35, K65(NLE), N68H, pH5.1
1yrf	Chicken villin subdomain HP-35, N68H, pH6.7
1yri	Chicken villin subdomain HP-35, N68H, pH6.4
1yu5	Crystal Structure of the Headpiece Domain of Chicken Villin
1yu7	Crystal Structure of the W64Y mutant of Villin Headpiece
1yu8	Crystal Structure of the R37A Mutant of Villin Headpiece
1zv6	NMR structure of the human dematin headpiece S74E mutant
2f4k	Chicken villin subdomain HP-35, K65(NLE), N68H, K70(NLE), PH9
2jm0	Solution structure of chicken villin headpiece subdomain containing a fluorinated side chain in the core
2k6m	Solution Structure of Human Supervillin Headpiece
2k6n	Solution Structure of Human Supervillin Headpiece, Minimized Average
2l3x	villin head piece domain of human ABLIM2
2ppz	NMR solution Structure of the Villin Headpiece Mutant G34L
2rjv	Crystal structure of the H41Y mutant of villin headpiece, P 21 21 21 space group
2rjw	The crystal structure of the H41Y mutant of villin headpiece, P61 SPACE GROUP.
2rjx	Crystal structure of the headpiece domain of chicken villin, P61 space group
2rjy	Crystal structure of villin headpiece, P21 21 21 space group
3iur	apPEP_D266Nx+H2H3 opened state
3j92	3J92
3mya	Crystal Structure of HP67 H41F - P61
3myc	Crystal Structure of HP67 H41F - P212121
3mye	Crystal Structure of HP67 L61GL
3nkj	Crystal Structure of HP67 L61G
3tjw	Crystal Structure of Quasiracemic Villin Headpiece Subdomain Containing (F5Phe10) Substitution
3trv	Crystal structure of quasiracemic villin headpiece subdomain containing (F5Phe17) substitution
3trw	Crystal structure of racemic villin headpiece subdomain crystallized in space group P-1
3try	Crystal structure of racemic villin headpiece subdomain in space group I-4c2
4cz3	4CZ3
4cz4	4CZ4
5i1n	5I1N
5i1o	5I1O
5i1p	5I1P
5i1s	5I1S

Links (links to other resources describing this domain)

• INTERPRO: IPR003128