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Biomedicine & Pharmacotherapy =... Sep 2023The pleckstrin homology [PH] domain is a structural fold found in more than 250 proteins making it the 11th most common domain in the human proteome. 25% of family... (Review)
Review
The pleckstrin homology [PH] domain is a structural fold found in more than 250 proteins making it the 11th most common domain in the human proteome. 25% of family members have more than one PH domain and some PH domains are split by one, or several other, protein domains although still folding to give functioning PH domains. We review mechanisms of PH domain activity, the role PH domain mutation plays in human disease including cancer, hyperproliferation, neurodegeneration, inflammation, and infection, and discuss pharmacotherapeutic approaches to regulate PH domain activity for the treatment of human disease. Almost half PH domain family members bind phosphatidylinositols [PIs] that attach the host protein to cell membranes where they interact with other membrane proteins to give signaling complexes or cytoskeleton scaffold platforms. A PH domain in its native state may fold over other protein domains thereby preventing substrate access to a catalytic site or binding with other proteins. The resulting autoinhibition can be released by PI binding to the PH domain, or by protein phosphorylation thus providing fine tuning of the cellular control of PH domain protein activity. For many years the PH domain was thought to be undruggable until high-resolution structures of human PH domains allowed structure-based design of novel inhibitors that selectively bind the PH domain. Allosteric inhibitors of the Akt1 PH domain have already been tested in cancer patients and for proteus syndrome, with several other PH domain inhibitors in preclinical development for treatment of other human diseases.
Topics: Humans; Pleckstrin Homology Domains; Binding Sites; Blood Proteins; Phosphoproteins; Protein Binding
PubMed: 37399719
DOI: 10.1016/j.biopha.2023.115024 -
European Journal of Ophthalmology Sep 2023In this report we illustrate the ophthalmologic assessment of two patients affected by Proteus Syndrome (PS), an extremely rare genetic disorder. Case #1 describes a 26...
In this report we illustrate the ophthalmologic assessment of two patients affected by Proteus Syndrome (PS), an extremely rare genetic disorder. Case #1 describes a 26 year old male patient followed for multiple ophthalmic anomalies: a limbal dermoid cyst, a unilateral cataract, bilateral nystagmus, severe myopia and unilateral optic nerve head drusen. Case #2 describes a 20 year old female patient referred to our Ophthalmology Department for a routine ophthalmologic evaluation after being treated for 3 years with Miransertib (an experimental AKT-pathway inhibitor). Both patients underwent a complete ophthalmologic examination and a multimodal imaging evaluation. The multimodal imaging approach has revealed useful to evaluate both cases in detail and to keep track of disease evolution over time, moreover providing helpful features to further characterize this rare syndrome.
Topics: Male; Female; Humans; Young Adult; Adult; Proteus Syndrome; Eye Abnormalities; Nystagmus, Pathologic; Diagnostic Imaging; Myopia; Abnormalities, Multiple
PubMed: 36113118
DOI: 10.1177/11206721221125852