Variable contribution of protein kinases to the generation of the human phosphoproteome: A global weblogo analysis

Abstract

In an attempt to evaluate the contribution of individual protein kinases to the generation of the human phosphoproteome, we performed a global weblogo analysis exploiting a database of 45641 phosphosites (80% pSer, 11% pTyr, 9% pThr). The outcome of this analysis was then interpreted by comparison with similar logos constructed from bona fide phospoacceptor sites of individual pleiotropic kinases. The main conclusions that were drawn are as follows: (i) the hallmarks surrounding phosphorylated Ser/Thr residues are more pronounced than and sharply different from those found around phosphorylated Tyr, which is consistent with the view that local consensus sequences are particularly important for substrate recognition by Ser/Thr protein kinases. (ii) Only six residues are positively selected around phosphorylated Ser/Thr residues, notably Pro (particularly at n+1), Glu, and to a lesser extent Asp, at various positions with special reference to n+3, Arg (and to a much lesser extent Lys), particularly at n-3 and n-5, and Ser, at various positions, particularly n+4 and n-4. (iii) This composite signature reflects the contribution of kinases whose bona fide substrates exhibit logos partially overlapping that of the whole phosphoproteome. These are Pro-directed kinases belonging to the CMGC group, some basophilic kinases belonging to the ACG and CAMK groups, phosphate-directed kinases such as GSK3 and members of the CK1 group and the individual highly acidophilic CK2. Collectively taken our data support the concept that a relatively small number of highly pleiotropic kinases contribute to the generation of the great majority of the human Ser/Thr phosphoproteome.