Autoinhibition of X11/Mint scaffold proteins revealed by the closed conformation of the PDZ tandem

Long, Jiafu; Feng, Wei; Wang, Rui; Chan, Li-Chong; Ip, Fanny C.F.; Xia, Jun; Ip, Nancy Y.; Zhang, Mingjie

doi:10.1038/nsmb958

Cited by 76 publications

(92 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been reported that tandem PDZ domains can form supramodules by direct inter-PDZ domain interactions, and such tandem PDZ supramodules include the PDZ12 and PDZ45 tandem from GRIP family proteins, the PDZ12 tandem from X11/Mint family proteins (23), and the PDZ12 tandem from syntenin (24) (Fig. S5B and C).…”

Section: Resultsmentioning

confidence: 99%

The structure of the harmonin/sans complex reveals an unexpected interaction mode of the two Usher syndrome proteins

Yan

Pan

Chen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

137

View full text Add to dashboard Cite

The hereditary hearing-vision loss disease, Usher syndrome I (USH1), is caused by defects in several proteins that can interact with each other in vitro. Defects in USH1 proteins are thought to be responsible for the developmental and functional impairments of sensory cells in the retina and inner ear. Harmonin/USH1C and Sans/USH1G are two of the USH1 proteins that interact with each other. Harmonin also binds to other USH1 proteins such as cadherin 23 (CDH23) and protocadherin 15 (PCDH15). However, the molecular basis governing the harmonin and Sans interaction is largely unknown. Here, we report an unexpected assembly mode between harmonin and Sans. We demonstrate that the N-terminal domain and the first PDZ domain of harmonin are tethered by a small-domain C-terminal to PDZ1 to form a structural and functional supramodule responsible for binding to Sans. We discover that the SAM domain of Sans, specifically, binds to the PDZ domain of harmonin, revealing previously unknown interaction modes for both PDZ and SAM domains. We further show that the synergistic PDZ1/SAM and PDZ1/carboxyl PDZ binding-motif interactions, between harmonin and Sans, lock the two scaffold proteins into a highly stable complex. Mutations in harmonin and Sans found in USH1 patients are shown to destabilize the complex formation of the two proteins.PDZ | SAM domain | scaffold proteins | USH1C | USH1G

show abstract

Section: Resultsmentioning

confidence: 99%

The structure of the harmonin/sans complex reveals an unexpected interaction mode of the two Usher syndrome proteins

Yan

Pan

Chen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

137

View full text Add to dashboard Cite

show abstract

“…Interestingly, the PDZ2 domain of APBA1 (also known as X11/MINT) contains a deletion of the same magnitude as the ZO-1 PDZ2 sequence. However, the NMR structure of this domain (Protein Data Bank code 1U39) reveals a monomeric PDZ domain (33), albeit with a rather short ␤2 and ␤3 strands, which are connected by a tight turn. Likewise, the second PDZ domain of SDCB1 (syntenin-1) is monomeric (34), despite having a comparable deletion in this region in comparison to ZO-1 PDZ2.…”

Section: Resultsmentioning

confidence: 99%

Domain Swapping within PDZ2 Is Responsible for Dimerization of ZO Proteins

Fanning

Lye

Anderson

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

ZO-1 is a multidomain protein involved in cell-cell junctions and contains three PDZ domains, which are necessary for its function in vivo. PDZ domains play a central role in assembling diverse protein complexes through their ability to recognize short peptide motifs on other proteins. We determined the structure of the second of the three PDZ domains of ZO-1, which is known to promote dimerization as well as bind to C-terminal sequences on connexins. The dimer is stabilized by extensive symmetrical domain swapping of ␤-strands, which is unlike any other known mechanism of PDZ dimerization. The canonical peptide-binding groove remains intact in both subunits of the PDZ2 dimer and is created by elements contributed from both monomers. This unique structure reveals an additional example of how PDZ domains dimerize and has multiple implications for both peptide binding and oligomerization in vivo.PDZ (PSD-95/Discs Large/zonula occludens-1) domains are modular protein-binding motifs that are found in bacteria, plants, and animals. They play a key role in scaffolding protein complexes through their ability to recognize short polypeptide motifs on other proteins and in some cases their ability to crosslink through dimerization. Although found in proteins with functions as diverse as cell signaling, cytoskeletal structure, cell polarity, and trafficking, many PDZ proteins are associated with the plasma membrane, where they mediate the assembly of specific subcellular domains like synapses and cell-cell junctions (reviewed in Ref. 1). Thus, the mechanisms for peptide binding and dimerization of PDZ domains have important implications for several fields.Although quite diverse at the primary sequence level, Ͼ150 known PDZ domain structures all share a conserved globular cluster of 5-6 ␤-strands and 1-2 ␣-helices (2). Peptide binding is mediated by a surface groove formed by an antiparallel ␤-strand (␤2) and ␣-helix (␣2) ((2) and reviewed in (3)). The majority of PDZ domain ligands are C-terminal peptides, which lie in this surface groove and form main chain interactions with ␣2 and ␤2. These interactions are highly specific and dependent on the terminal 3-4 amino acids of the peptide ligand (4). However, other residues within the ligand may also contribute to the specificity and affinity of the PDZ-ligand interaction (5). In addition, other binding modalities have also been characterized. For example, some PDZ domains can bind to internal peptide sequences or phosphoinositides (6 -8). Finally, a limited number of PDZ domains can directly bind another PDZ domain to form homo-and hetero-oligomers (9 -12). In contrast to the conserved mechanism of C-terminal peptide binding, there exist several distinct mechanisms for dimerization.PDZ domains are particularly important in the organization of cellular tight junctions (TJ).3 Tight junctions form the paracellular barrier to the movement of ions, macromolecules, and cells across both endothelia and epithelia (13). Although several different classes of PDZ proteins are localized ...

show abstract

“…Previous NMR studies observed intramolecular contacts between the Mint1 C-terminal tail and the PDZ1 domain, which blocks its ability to bind exogenous targets (25). Phosphorylation of a Tyr residue at the penultimate position in the C-terminal tail was proposed to disrupt its association with the PDZ1 domain, thereby liberating the PDZ1 domain to engage other ligands (25). Our data now show a different type of intramolecular inhibition within Mint1 whereby the region C-terminally adjacent to the Mint1 PTB domain forms an α-helix that occludes the APP binding site.…”

Section: Discussionmentioning

confidence: 99%

Autoinhibition of Mint1 adaptor protein regulates amyloid precursor protein binding and processing

Matos

Xu²,

Dulubova

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Mint adaptor proteins bind to the amyloid precursor protein (APP) and regulate APP processing associated with Alzheimer's disease; however, the molecular mechanisms underlying Mint regulation in APP binding and processing remain unclear. Biochemical, biophysical, and cellular experiments now show that the Mint1 phosphotyrosine binding (PTB) domain that binds to APP is intramolecularly inhibited by the adjacent C-terminal linker region. The crystal structure of a C-terminally extended Mint1 PTB fragment reveals that the linker region forms a short α-helix that folds back onto the PTB domain and sterically hinders APP binding. This intramolecular interaction is disrupted by mutation of Tyr633 within the Mint1 autoinhibitory helix leading to enhanced APP binding and β-amyloid production. Our findings suggest that an autoinhibitory mechanism in Mint1 is important for regulating APP processing and may provide novel therapies for Alzheimer's disease.M ints [also known as X11s or amyloid precursor protein (APP) binding, family A] are a family of adaptor proteins encoded by three genes: neuron-specific Mint1 and Mint2, and the ubiquitously expressed Mint3 (1, 2). Mints consist of a divergent N-terminal region and conserved C-terminal sequences composed of a phosphotyrosine binding (PTB) domain and two tandem PDZ (postsynaptic density-95/discs large/zona occludens-1) domains. The PTB domain of all Mints interacts directly with a conserved YENPTY cytoplasmic motif of the APP that is essential for regulating APP trafficking and processing (3-6). APP is a type I transmembrane protein that is sequentially cleaved by site-specific proteases (7-10). Abnormal processing of APP generates Aβ peptides leading to the accumulation of extracellular plaques that are characteristic of Alzheimer's disease (AD). β-Secretase is the first amyloidogenic cleavage, generating a soluble APP ectodomain (sAPPβ) and a C-terminal fragment (CTFβ). CTFβ is subsequently cleaved by γ-secretase (a protein complex of anterior pharyx defective 1, nicastrin, presenilin, and presenilin enhancer 2) to release the small peptides Aβ40 and Aβ42, the latter having an increased propensity to form amyloid aggregates found in the brains of AD patients (11)(12)(13)(14). Alternatively, APP is sequentially cleaved by α-secretase within the Aβ region then γ-secretase, which initiates the nonamyloidogenic or nontoxic pathway (9, 10).Considerable evidence indicates that the APP-Mint interaction is biologically significant because loss of each individual Mint protein delays age-dependent production of amyloid plaques in transgenic AD mouse models (15). Past studies have indicated that the N-and C-terminal regions of Mints play an important role in regulating APP binding and cleavage events based on deletion analysis of Mints in a heterologous expression system (6, 16). The Mint N terminus was shown to promote APP binding and Aβ production, whereas the C-terminal region disrupted PTB-mediated binding to APP and decreased Aβ peptides (6, 16). However, the structural basis ...

show abstract

Autoinhibition of X11/Mint scaffold proteins revealed by the closed conformation of the PDZ tandem

Cited by 76 publications

References 48 publications

The structure of the harmonin/sans complex reveals an unexpected interaction mode of the two Usher syndrome proteins

The structure of the harmonin/sans complex reveals an unexpected interaction mode of the two Usher syndrome proteins

Domain Swapping within PDZ2 Is Responsible for Dimerization of ZO Proteins

Autoinhibition of Mint1 adaptor protein regulates amyloid precursor protein binding and processing

Contact Info

Product

Resources

About