Diseases mediated by linear motifs
Several diseases are known which are caused by one or more mutations in linear motifs mediating important interactions.
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.
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" 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
(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" 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].
IMAGE syndrome is a rare multisystem disorder characterized by intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies [Vilain, E. et al. 1999]. The disease locus was mapped to missense mutations in the carboxy terminus of the "Cyclin-dependent kinase inhibitor 1C" protein CDN1C_HUMAN [Arboleda et al. 2012]. This protein plays a key role in the inhibition of cell-cycle progression and is therefore tightly regulated and repressed in most tissues. It contains a CRL4-Cdt2 binding PIP degron at position 270 which is recognized by the CRL4Cdt2 ubiquitin ligase in a PCNA-dependent manner. Mutations in this motif result in excess inhibition of growth and differentiation.
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)
Von Willebrand Disease
"von Willebrand factor" VWF_HUMAN is a large multimeric glycoprotein containing more than 2000 amino acids.
The protein undergoes N-glycosylation in the endoplasmic reticulum resulting in the formation of dimers
which in turn are arranged into multimers by cysteine cross-linking.
The mutation of Cys1149 results in a decrease in the secretion of coexpressed normal VWF, and this mutation is proposed to cause intracellular retention of pro-VWF heterodimers (Eikenboom et al. 1996) causing "von Willebrand disease, type 1 (VWD1)"
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].
Via its role in ectodomain shedding, "Disintegrin and metalloproteinase domain-containing protein 15" Adam15 has been implicated in several diseases, including cancer [Najy AJ, 2008]. Kleino et al. investigated the different alternatively spliced versions of Adam15 and found that different isoforms showed profound differences in interaction partner selection: Exons 18-23 contain different proline-rich regions featuring one or more LIG_SH3 binding motifs and different isoforms bind to specific SH3 domains in different interaction partners: While ADAM15 isoforms i4, i5, and i6 showed a selective ability for strong binding to nephrocystin, ADAM15 i3, containing a unique proline motif not present in other ADAM15 isoforms, bound preferentially to the SH3 domain of Hck tyrosine kinase, whereas the isoform i1, lacking apparent proline-rich clusters, did not bind SH3 domains at all. [Kleino et al., 2009]. The mis-regulation of alternative exon usage of Adam15 can thus significantly influence the protein's interactions and can ultimately lead to cancer [Ortiz et al., 2004].
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.
The protein aquaporin-0 is a water channel that constitutes more than 60% of the membrane protein content of fibre cells in the ocular lens. Mutations in this protein can cause severely reduced vision caused by clouding of the ocular lens, called cataract. Water permeability of aquaporin-0 is decreased by binding of CaM to the C-terminal cytoplasmic region between residues 225 and 263. Gold et al. showed that "Protein kinase A-anchoring protein 2" AKAP2 binds to aquaporin-0 and thus brings it into proximity with PKA (Protein Kinase A) [Gold, 2011]. In turn, PKA is able to phosphorylate residue S235 [Schey, 1999] of aquaporin-0 which prevents binding of aquaporin-0 to calmodulin (CaM) which subsequently increases water influx through the channel. The (conservative) mutation of an arginine to lysine at position 235 prohibits the phosphorylation of Ser235 and favours CaM binding to sustain the closed conformation of the water channel leading to fibre cell swelling, severe light scattering and early onset of cataracts [Lin, 2007].
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 EspFu 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 EspFu protein, EHEC is able to interact with multiple N-WASP proteins simultaneously and thus potently stimulate actin polymerization.
The protein "lethal factor" (LEF_BACAN) is a metalloprotease that specifically targets MKKs (mitogen-activated protein kinase kinases) MEK1, MEK2, MKK3, MKK4, MKK6, and MKK7. These kinases are important regulators of signal transduction as they phosphorylate and thus activate specific MAPKs (such as ERK1, ERK2, p38 or JNK). Bacillus anthracis' "lethal factor" cleaves its MKK substrates within or close to the MAPK docking sites (eg. annotated at 3-11 in MEK1), thus effectively preventing the MKK to dock to its MAPK [Bardwell, 2004].