8hga | pdb_00008hga
Monomer structure of transforming growth factor beta induced protein (TGFBIp) G623R fibril
Structural highlights
DiseaseBGH3_HUMAN Defects in TGFBI are the cause of epithelial basement membrane corneal dystrophy (EBMD) [MIM:121820; also known as Cogan corneal dystrophy or map-dot-fingerprint type corneal dystrophy. EBMD is a bilateral anterior corneal dystrophy characterized by grayish epithelial fingerprint lines, geographic map-like lines, and dots (or microcysts) on slit-lamp examination. Pathologic studies show abnormal, redundant basement membrane and intraepithelial lacunae filled with cellular debris. Although this disorder usually is not considered to be inherited, families with autosomal dominant inheritance have been identified.[1] Defects in TGFBI are the cause of corneal dystrophy Groenouw type 1 (CDGG1) [MIM:121900; also known as corneal dystrophy granular type. Inheritance is autosomal dominant. Corneal dystrophies show progressive opacification of the cornea leading to severe visual handicap.[2] Defects in TGFBI are the cause of corneal dystrophy lattice type 1 (CDL1) [MIM:122200. Inheritance is autosomal dominant. Defects in TGFBI are a cause of corneal dystrophy Thiel-Behnke type (CDTB) [MIM:602082; also known as corneal dystrophy of Bowman layer type 2 (CDB2). Defects in TGFBI are the cause of Reis-Buecklers corneal dystrophy (CDRB) [MIM:608470; also known as corneal dystrophy of Bowman layer type 1 (CDB1).[3] [4] [5] Defects in TGFBI are the cause of lattice corneal dystrophy type 3A (CDL3A) [MIM:608471. CDL3A clinically resembles to lattice corneal dystrophy type 3, but differs in that its age of onset is 70 to 90 years. It has an autosomal dominant inheritance pattern.[6] [7] Defects in TGFBI are the cause of Avellino corneal dystrophy (ACD) [MIM:607541. ACD could be considered a variant of granular dystrophy with a significant amyloidogenic tendency. Inheritance is autosomal dominant. FunctionBGH3_HUMAN Binds to type I, II, and IV collagens. This adhesion protein may play an important role in cell-collagen interactions. In cartilage, may be involved in endochondral bone formation. Publication Abstract from PubMedTGFBI-related corneal dystrophy (CD) is characterized by the accumulation of insoluble protein deposits in the corneal tissues, eventually leading to progressive corneal opacity. Here we show that ATP-independent amyloid-beta chaperone L-PGDS can effectively disaggregate corneal amyloids in surgically excised human cornea of TGFBI-CD patients and release trapped amyloid hallmark proteins. Since the mechanism of amyloid disassembly by ATP-independent chaperones is unknown, we reconstructed atomic models of the amyloids self-assembled from TGFBIp-derived peptides and their complex with L-PGDS using cryo-EM and NMR. We show that L-PGDS specifically recognizes structurally frustrated regions in the amyloids and releases those frustrations. The released free energy increases the chaperone's binding affinity to amyloids, resulting in local restructuring and breakage of amyloids to protofibrils. Our mechanistic model provides insights into the alternative source of energy utilized by ATP-independent disaggregases and highlights the possibility of using these chaperones as treatment strategies for different types of amyloid-related diseases. Release of frustration drives corneal amyloid disaggregation by brain chaperone.,Low JYK, Shi X, Anandalakshmi V, Neo D, Peh GSL, Koh SK, Zhou L, Abdul Rahim MK, Boo K, Lee J, Mohanram H, Alag R, Mu Y, Mehta JS, Pervushin K Commun Biol. 2023 Mar 30;6(1):348. doi: 10.1038/s42003-023-04725-1. PMID:36997596[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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