Diseases mediated by linear motifs

Several diseases are known which are caused by one or more mutations in linear motifs mediating important interactions.

Noonan Syndrome

The developmental disorder "Noonan Syndrome" can be caused by mutations in Raf-1 which abrogate the interaction with 14-3-3 proteins mediated by corresponding motifs and thereby deregulate the Raf-1 kinase activity [Pandit et al., 2007]. The Raf-1 sequence features two LIG_14-3-3_1 binding sites, which are annotated at 256-261 and 618-623.

Noonan-like Syndrome

A S->G mutation at position 2 creates a novel MOD_NMyristoyl site (irreversible modification) resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation [Cordedu et al., 2007].

Usher's Syndrome

"Usher's Syndrome" is the most frequent cause of hereditary deaf-blindness in humans [Eudy and Sumegi, 1999], affecting one child in 25 000. This disease can be caused by mutations in either PDZ domains in Harmonin or the corresponding PDZ interaction motifs in the SANS protein (annotated at 456-461) [Weil et al., 2003, Kalay et al., 2005].

Another example implicating PDZ domains is "familial hypomagnesemia with hypercalciuria and nephrocalcinosis" (FHWHN), an autosomal recessive wasting disorder of renal Mg²⁺ and Ca²⁺ that leads to progressive kidney failure. Here, motifs mediating interaction to PDZ domains are mutated in Claudin 16, abolishing important interactions to the scaffolding protein ZO-1 resulting in lysosomal mislocalization of the protein [Müller et al., 2003, Müller et al., 2006].

Liddle's Syndrome

"Liddle's Syndrome" has been implicated with autosomal dominant activating mutations in the WW interaction motif in the β- (SCNNB_HUMA) and γ- (SCNNG_HUMA) subunits of the "epithelial sodium channel" ENaC [Warnock, 1998]. These mutations abrogate the binding to the ubiquitin ligase NEDD4-2, thereby inhibiting channel degradation and prolonging the half-life of ENaC, ultimately resulting in increased Na⁺ reabsorption, plasma volume extension and hypertension [Furuhashi et al., 2005, Wang et al., 2007].

Golabi-Ito-Hall Syndrome

This syndrome is caused by a missense mutation in the PQBP1 gene exchanging a Tyrosine into Cysteine in the WW interaction domain of PQBP1_HUMAN [Lubs et al., 2006, Tapia et al., 2010].

Autosomal Dominant Retinitis Pigmentosa

Under normal circumstances, rhodopsin, associated proteins and lipids are sorted on post-Golgi membranes into a specialized segment of rods, where they perform their important function in signalling upon stimulation with light. Mutations in the C-terminal region of rhodopsin (OPSD_HUMAN) can lead to severe forms of autosomal dominant retinitis pigmentosa in humans by distroying the conserved terminal motif 'QV[SA]PA', resulting in aberrant sub-cellular localisation of rhodopsin [Deretic, 1998]. (For more information about ciliary targeting motifs, see TRG_Cilium_Arf4_1)

Cancer

β-catenin is a multifunctional protein of the cadherin complex and is an important component of the Wnt signalling pathway. It can act as a cofactor for the TCF/LEF transcription factors and can activate wnt-responsive target genes such as cyclin D1, MMP7, COX2 and others [Lustig et al. 2003]. Mutations in the catenin-gene (CTNNB1) are implicated in various cancers, such as breast cancer [Wang et. al 2008]. Upon phosphorylation by GSK3β at positions S33, S37 and T41 β-catenin binds to E3 ubiquitin ligase β-TrCP via the LIG_SCF-TrCP1_1 phospho-degron (annotated at 32-37) and undergoes proteosomal degradation. Mutations of residue D32, S33 and G34 mediate β-catenin oncogenic activity by preventing degradation and thus stabilizing it [Provost 2005].

X-linked severe congenital neutropenia

Members of the Wiskott-Aldrich syndrome protein WASP family are central hubs in the signaling networks activating the ubiquitous actin-nucleating machine, the Arp2/3 complex [Padrick, 2010]. CDC42 is the most important activator of WASP, binding to its GBD domain and thus disrupting the auto-inhibition of N-WASP. Devriendt et al. describe a novel disease, X-linked severe congenital neutropenia, which is caused by a novel L270P mutation in the GBD region on WASP [Devriendt 2001]. The mutation abrogates the auto-inhibitory mechanism and constitutively activates the Arp2/3 complex.

Pathogens abusing linear motifs

Enterohaemorrhagic Escherichia coli

The Wiskott-Aldrich syndrome protein (N-WASP) is an important regulator of the actin cytoskeleton: An intramolecular auto-inhibitory mechanism is disrupted by interaction with the Rho-GTPase CDC42, which in turn leads to stimulation the actin-nucleating activity of the Arp2/3 complex. Enterohaemorrhagic Escherichia coli (EHEC) encodes the EspF_u protein which is able to mimic the autoinhibitory element within N-WASP and thus activate N-WASP with a potency that is orders of magnitude higher than single endogenous activators [Prehoda, 2000, Sallee, 2008, Padrick, 2010]. By using multiple repeats in one EspF_u protein, EHEC is able to interact with multiple N-WASP proteins simultaneously and thus potently stimulate actin polymerization.