The alphabet of intrinsic disorder: II. Various roles of glutamic acid in ordered and intrinsically disordered proteins

Uversky, Vladimir N

Pyoderma gangrenosum and Glu250Gln mutation in PSTPIP1. Pyoderma gangrenosum is a condition that causes tissue to become necrotic, causing deep ulcers that usually occur on legs. Pyoderma gangrenosum is one of the most common extra-intestinal manifestations of chronic inflammatory bowel disease. 246 The disease is caused by the alterations in the pathway that links the members of the proline-rich, glutamic acid-rich, serine-rich and threonine-rich (PEST) family of protein tyrosine phosphatases (which are critical regulators of adhesion and migration) to their substrates. A major player in this pathway is a cytoskeleton-associated adaptor protein, namely proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1, also known as CD2-binding protein 1, CD2BP1). 246 Defects in PSTPIP1 are the cause of PAPA syndrome (PAPAS), also known as pyogenic sterile arthritis, pyoderma gangrenosum and acne or familial recurrent arthritis (FRA). 247 PAPAS is characterized by an autosomal dominant inheritance of early onset, primarily affecting skin and joint tissues. Missense mutations Glu250-Gln and Ala230-Thr in PSTPIP1/CD2BP1 were identified in two families. 247 These mutations were shown to affect the ability of PSTPIP1to interact with its natural partners. 247, 248 and BEAF32. 240 Although Cp190 is a large protein (1,096 residues) that possesses a complex multidomain structure, only three domains were shown to be essential for the insulator function and for the viability of flies: the BTB/POZ domain, an aspartic acid-rich (D-rich) region and a C-terminal glutamic acid-rich (E-rich) region. 240 Here, the N-terminal Cp190 fragment containing the BTB/POZ domain and the D-rich region was shown to be involved in regulation of the Cp190 interaction with insulator complexes, whereas the C-terminally located E-rich region was necessary for the Cp190 dissociation from chromosomes during heat-shock. 240 Importantly, the 131 glutamic acids are not equally distributed within the protein, with the N-terminal half containing just 26 glutamic acids and with the remaining 105 glutamates being concentrated within the C-terminal half of Cp190. Therefore, although the overall glutamic acid content of this protein is 12%, its C-terminal half is especially enriched in these residues (19.2%). Also, this uneven distribution is seen not only for Glu, but for all the charged residues. In fact, the N-terminal fragment (residues 1-548) has a net charge of +18 (Asp + Glu = 25 + 26 = 51; Arg + Lys = 31 + 38 = 69), whereas the C-terminal half of Cp190 (residues 549-1096) has a net charge of −120 (Asp + Glu = 62 + 105 = 167; Arg + Lys = 8 + 39 = 47).