ELM Details - LIG_CAP-Gly

LIG_CAP-Gly_1

Functional site class:	CAP-Gly Domain Ligand
Functional site description:	CAP-Gly domains are central to the regulatory interactions at the plus ends of microtubules. They are found in a number of microtubule-interacting proteins with very diverse architectures. CAP-Gly domains harboring an intact GKNDG binding site motif recognise a C-terminal EEY/F$ motif that, in the case of alpha-tubulin, is subject to a cycle of tyrosination/detyrosination.
ELM(s):	LIG_CAP-Gly_1
LIG_CAP-Gly_1 description:	Short, acidic and aromatic carboxy terminal sequence found in a small group of microtubule-associated-proteins. The EEY/F$ motif is highly conserved and so far limited to a few known proteins, alpha-tubulin, EB proteins and CLIP170. The current regular expression is mainly modelled on the metazoan sequences. While there is the possibility that the motif has drifted in other lineages, it retrieves almost all alpha-tubulins in Swiss-Prot. It has a low but finite rate of false positives.
Pattern:	[ed].{0,2}[ed].{0,2}[edq].{0,1}[YF]$
Present in taxon(s):	Eukaryota
Not represented in taxon(s):

See instances for LIG_CAP-Gly_1

Abstract

The cytoskeleton-associated protein-glycine-rich domain (CAP-Gly; Pfam accession code PF01302) is a small, approximately 80-residue protein module conserved in organisms from yeast to human. CAP-Gly domains have central functions in many proteins, including cytoplasmic linker proteins (CLIPs and CLIPRs), the large subunit of the dynactin complex (DCTN1, or p150glued), tubulin folding cofactors B and E, centrosome-associated protein-350 (CAP350), the kinesin protein KIF13b and the familial cylindromatosis tumor suppressor CYLD. These proteins are implicated in essential cellular processes such as chromosome segregation, establishment and maintenance of cell polarity, intracellular organelle and vesicle transport, cell migration, intracellular signaling and oncogenesis.

The CAP-Gly domains of microtubule-associated-proteins (MAPs) are characterized by the conserved GKNDG motif which is responsible for targeting to the carboxy terminal EEY/F sequence motifs of CLIP170, EB proteins, and alpha-tubulin. The CAP-Gly–EEY/F interaction is essential for the recruitment of the dynactin complex by CLIP170 (through p150glued) and for activation of CLIP170. Furthermore, in most eukaryotic cells, the EEY/F tail of alpha-tubulin is subjected to an enzymatic detyrosination-tyrosination cycle in which the C-terminal tyrosine is repeatedly cleaved and added back. Suppression of this cycle leads to defects in spindle positioning, abnormal cell morphology, disorganized neuronal networks and tumour progression, underscoring the importance of this post-translational modification. Only very recently, alpha-tubulin tyrosination has been linked to the ability of the microtubule plus end to recruit the CAP-Gly proteins p150glued, CLIP170 and CLIP115. Thus, the CAP-Gly-EEY/F interaction plays a fundamental role in the tubulin detyrosination-tyrosination cycle by controlling CAP-Gly proteins and as a consequence microtubule function.

Selected references

Galjart N

CLIPs and CLASPs and cellular dynamics.

Nat Rev Mol Cell Biol 2005 Jun;6(6) : 487-98.

PMID: 15928712

Goodson HV, Skube SB, Stalder R, Valetti C, Kreis TE, Morrison EE, Schroer TA

CLIP-170 interacts with dynactin complex and the APC-binding protein EB1 by different mechanisms.

Cell Motil Cytoskeleton 2003 Jul;55(3) : 156-73.

PMID: 12789661

Hayashi I, Plevin MJ, Ikura M

CLIP170 autoinhibition mimics intermolecular interactions with p150Glued or EB1.

Nat Struct Mol Biol 2007 Oct;14(10) : 980-1.

PMID: 17828275

Hayashi I, Wilde A, Mal TK, Ikura M

Structural basis for the activation of microtubule assembly by the EB1 and p150Glued complex.

Mol Cell 2005 Aug 19;19(4) : 449-60.

PMID: 16109370

Honnappa S, Okhrimenko O, Jaussi R, Jawhari H, Jelesarov I, Winkler FK, Steinmetz MO

Key interaction modes of dynamic +TIP networks.

Mol Cell 2006 Sep 1;23(5) : 663-71.

PMID: 16949363

Komarova Y, Lansbergen G, Galjart N, Grosveld F, Borisy GG, Akhmanova A

EB1 and EB3 control CLIP dissociation from the ends of growing microtubules.

Mol Biol Cell 2005 Nov;16(11) : 5334-45.

PMID: 16148041

Lansbergen G, Komarova Y, Modesti M, Wyman C, Hoogenraad CC, Goodson HV, Lemaitre RP, Drechsel DN, van Munster E, Gadella TW Jr, Grosveld F, Galjart N, Borisy GG, Akhmanova A

Conformational changes in CLIP-170 regulate its binding to microtubules and dynactin localization.

J Cell Biol 2004 Sep 27;166(7) : 1003-14.

PMID: 15381688

Li S, Finley J, Liu ZJ, Qiu SH, Chen H, Luan CH, Carson M, Tsao J, Johnson D, Lin G, Zhao J, Thomas W, Nagy LA, Sha B, DeLucas LJ, Wang BC, Luo M

Crystal structure of the cytoskeleton-associated protein glycine-rich (CAP-Gly) domain.

J Biol Chem 2002 Dec 13;277(50) : 48596-601.

PMID: 12221106

Peris L, Thery M, Faure J, Saoudi Y, Lafanechere L, Chilton JK, Gordon-Weeks P, Galjart N, Bornens M, Wordeman L, Wehland J, Andrieux A, Job D

Tubulin tyrosination is a major factor affecting the recruitment of CAP-Gly proteins at microtubule plus ends.

J Cell Biol 2006 Sep 11;174(6) : 839-49.

PMID: 16954346

Weisbrich A, Honnappa S, Jaussi R, Okhrimenko O, Frey D, Jelesarov I, Akhmanova A, Steinmetz MO

Structure-function relationship of CAP-Gly domains.

Nat Struct Mol Biol 2007 Oct;14(10) : 959-67.

PMID: 17828277

This ELM has been assigned the following Gene Ontology (GO) terms for biological process, cellular component and molecular function.

Biological Process

  establishment and/or maintenance of microtubule cytoskeleton polarity

GO:0030951

  microtubule cytoskeleton organization and biogenesis

GO:0000226

  microtubule-based movement

GO:0007018

  microtubule-based process

GO:0007017

  regulation of microtubule-based process

GO:0032886

  plus-end directed microtubule sliding

GO:0031535

  microtubule polymerization or depolymerization

GO:0031109

Cellular Component

  cytosol

GO:0005829

  microtubule

GO:0005874

Molecular Function

  microtubule plus-end binding

GO:0051010

  protein domain specific binding

GO:0019904

Instances for LIG_CAP-Gly_1

Sequence	Position	Subsequence (Click for evidence information)	PDB	Gene Name	Protein Description	Organism
TBA1A_HUMAN	443-451	DSVEGEGEEEGEEY	2E4H	Name=TUBA1A; Synonyms=TUBA3;	Tubulin alpha-1A chain (Tubulin B-alpha-1) (Tubulin alpha-3 chain) (Alpha-tubulin 3).	Homo sapiens (Human).
CLIP1_HUMAN	1423-1427	ATNCNDDETF	2PZO	Name=CLIP1; Synonyms=CYLN1, RSN;	CAP-Gly domain-containing linker protein 1 (Restin) (Cytoplasmic linker protein 170 alpha-2) (CLIP-170) (Reed-Sternberg intermediate filament-associated protein) (Cytoplasmic linker protein 1).	Homo sapiens (Human).
MARE1_HUMAN	263-268	EGGPQEEQEEY	2HKQ 1TXQ	Name=MAPRE1;	Microtubule-associated protein RP/EB family member 1 (APC-binding protein EB1) (End-binding protein 1) (EB1).	Homo sapiens (Human).