JAK Structure and Localization

The JAK kinases are relatively large proteins, with molecular weights of approximately 120 to 140 kDa. Seven regions

Jak Kinase

Figure 2 Cytokine receptor families and associated JAKs. From left to right, (1) the homodimeric hormone receptors, which signal via JAK2; (2) the IL-3 family of receptors, each having a unique ligand binding a chain and sharing a common beta (Pc) subunit associated with JAK2; (3) the IL-6 subfamily of receptors, which have a common gp130 subunit that can interact with different members of the JAK family; (4) the IL-2 receptor family, which shares a common gamma (yc) subunit and is the only cytokine receptor subunit that interacts with JAK3. The receptor-specific a or P subunit binds JAK1. The type II cytokine receptors, the interferon y (5) and interferon a/p (6) receptors, signal via JAK1, JAK2, and Tyk2. (Adapted from Pellegrini, S. and Dusanter-Fourt, I., Eur. J. Biochem., 248, 615-633, 1997.)

Figure 2 Cytokine receptor families and associated JAKs. From left to right, (1) the homodimeric hormone receptors, which signal via JAK2; (2) the IL-3 family of receptors, each having a unique ligand binding a chain and sharing a common beta (Pc) subunit associated with JAK2; (3) the IL-6 subfamily of receptors, which have a common gp130 subunit that can interact with different members of the JAK family; (4) the IL-2 receptor family, which shares a common gamma (yc) subunit and is the only cytokine receptor subunit that interacts with JAK3. The receptor-specific a or P subunit binds JAK1. The type II cytokine receptors, the interferon y (5) and interferon a/p (6) receptors, signal via JAK1, JAK2, and Tyk2. (Adapted from Pellegrini, S. and Dusanter-Fourt, I., Eur. J. Biochem., 248, 615-633, 1997.)

JAKs

FERM domain

SH2 domain

Pseudo kinase

Kinase domain

Figure 3 Structure of JAKs. The JAK family of kinases contains seven conserved sequence regions, JAK homol-ogy (JH) domains 1 to 7. The JH1 domain is a tyrosine kinase domain, and the JH2 domain is a pseudokinase domain without catalytic activity but is essential for normal JAK function. The region encompassing the C-terminal portion of JH4 and the JH3 domain has sequence similarity with SH2 domains. The N-terminal region of JAKs contains a FERM domain, which is critical for their association with the receptor and for kinase function.

with conserved sequence have been identified within the JAKs, and these are designated JAK homology (JH) domains 1 to 7 (Fig. 3) [4]. JH1 refers to the functional kinase domain, and JH2 is the pseudokinase domain. Sequence analysis showed that the region spanning JH7 to the N-terminal half of JH4 contains a domain known as the FERM domain (band four-point-one, ezrin, radixin, moesin homology domain) (Fig. 3) [15]. In other proteins, this domain of «300 amino acids is involved in binding to the cytoplasmic regions of several transmembrane proteins, thereby localizing the FERM domain containing protein to the plasma membrane [16]. The FERM domain of JAKs is now known to be responsible for anchoring JAKs to the cytoplasmic region of cytokine receptors [17,18]. Crystal structures of the FERM domains of radixin [19] and moesin [20] reveal three subdomains that form a compact, clover-shaped structure. Although there is only a low level of sequence identity between this segment of the JAKs and other FERM domains, there are several conserved blocks of sequence within this region [15], suggesting that the overall structures may be similar. The region spanning the C-terminal part of JH4 to JH3 has sequence similarity to

Src homology 2 (SH2) domains, the modular phosphotyro-sine binding domains [21,22]. As with the FERM domain, the level of sequence similarity of the JAK SH2-like domain with other SH2 domains is very low, and to date the function of this domain in JAK kinases is not known.

Certain mutant forms of JAK3 isolated from patients with severe combined immune deficiency (SCID) revealed point mutations in the FERM domain [18]. Interestingly, these mutations not only disrupted kinase-receptor association, but also abrogated adenosine triphosphate (ATP) binding to the kinase domain, thereby destroying kinase activity. The mutation Gly 341 to Glu that maps to the FERM domain of the Drosophila Hop protein (a JAK homolog) has been shown to hyperactivate the kinase [23]. Furthermore, mutations in the pseudokinase domain of JAKs have been shown to alter the activity of the kinase, with different mutations resulting in either a loss of kinase activity [24] or a hyperactive kinase [25]. These results suggest a complex interplay between the various domains of JAKs, an understanding of which will require a crystal structure of the entire JAK molecule.

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