Protein tether for a subset of proteins

Protein
kinases are a large family of enzymes that catalyze the transfer of phosphate
from ATP to serine, threonine, and tyrosine residues of their substrate
proteins. Protein kinases are found in all eukaryotes from yeast to mammals.
They are involved in many aspect of cell as they play a critical role in signaling
and other major cellular processes. While each specific kinase is thought to
have a specific function, there are many conserved domains among kinases
regarding their structures and catalytic mechanisms. The Phosphoinositide
3-kinases (PI3Ks) related protein kinases (PIKKs) are a family of protein
kinases with a large range of important cellular functions. PI3Ks phosphorylate
the inositol ring on the 3 position, which creates a docking site for proteins.
There are eight catalytic PI3K subunits that are divided into three classes
based on the sequence alignment and domain structures (Fig.1: a,b). The class
III PI3K is the oldest PI3K and is the only one found in yeast and plants with
a Vps34 domain structure that phosphorylates phosphatidylinositol to generate
PI3P. The class II PI3Ks with a CII  domain structure are localized in endosomes,
but their function is still not well understood. The class I PI3Ks are heterodimeric
proteins with a p110 domain structure. The class I PI3K subunits
are further subdivided into class IA and IB. the class IA subunits are
associated with a SH2-containing regulatory subunits of PIP3. PIP3 acts as a membrane
tether for a subset of proteins with one or more pleckstrin homology (PH) domains.
PH domains need to have enough affinity for the PIP3 in order for it to be
selectively regulated by class I PI3Ks. In mammals, about 40 of the 200+
proteins with PH domains can be controlled by PIP3. However most of the focus
is contributed to the regulation of the Akt pathway and its role in controlling
the activation of the mammalian target of rapamycin (mTOR). mTOR is  a serine/threonine kinase in the PI3K-related
kinase (PIKK). It is a central regulator of cellular metabolism, growth and
survival in response to hormones, growth factors, nutrients, energy, and stress
signals. mTOR directly or indirectly regulates the phosphorylation of many
proteins. It functions as part of two structurally and functionally distinct
signaling complexes mTOR complex 1 (mTORC1) and mTOR complex2 (mTORC2). Activated
mTORC1 upregulates protein synthesis and is mainly involved in cell growth (Fig.
2.a). It is defined by its three core components: mTOR, Raptor (regulator
associated with mTOR), and mLST8.  Raptor
facilitates substrate recruitment to mTORC1 while the mLST8 associate with the
catalytic domain of mTORC1, which stabilize the kinase activation loop that is
essential for mTORC1 function (figure2b). mTORC2 may regulate other cellular
processes including the organization of the cytoskeleton. It plays a critical
role in the phosphorylation of AKT1, a pro-survival effector of PI3K (Fig. 2.a).
mTOR2 also contains  mTOR and mSLT8, but
instead of Raptor mTORC2 contains Rictor, a rapamycin insensitive companion of
mTOR (Fig. 2.c).

·     
Overall
structure of mTOR kinase.

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The mTOR protein
is a 289-KDa that belongs to the PI3K-related kinase family and is conserved
throughout evolution with a kinase domain similar to the PI3Ks. The conserved
N-terminal of the mTOR kinase domain, long helical repeats, is shared among all
PIKKs. Recently, a crystal structure of the mTOR kinase domain in complex with
mST8 has been resolved at 3.2  resolution (Fig.3). The structure shows the
two-lobe catalytic core found in both mTORC1 and mTORC2. It also shows the FRB
(FK506-rapamycin binding) domain, the FATC (FRAPP, ATM, TOR at C-terminus)
domain, the LBE (LST8 binding element), and the KAL (activation loop helix) are all PIKK
specific features. Also, the crystal structure (Fig.3) shows a potion of he
N-teminal helical repeats with the FAT domain. The interaction between the
Kinase domain (KD) and the FAT domain is established through hydrogen bonds
which is thought to be important for the kinase domain structure and activity,
and are common features of all PIKKs.

There are three
distinct clusters of activating mutation located within the kinase domain and
in the interface between the kinase domain and the FAT domain. Mutations in
this area are believed to make the end of the catalytic cleft less protected by
either weakening the interaction between the helices or decreasing the kinase
domain interactions. This allows mTOR to become more active toward the
physiological substrates 4E-BP1 and S6K1 as well as increases its kinase
activity by having more access to the catalytic site.

One side of the
activation loop packs with the k9b insertion, and the other side packs
with FATC (Fig.2b). The FATC’s N-terminal half forms a helix (kthat is present in the PI3K structures,
but its C-terminal half is absent from the PI3Ks. The FATC’s C-terminal forms
three short helices that pack with the activation loop on one side and with the
LBE on the other side (Fig.2b). The FATC and activation loop sequences are
conserved among the PIKKs, but not the LBE. However, all PIKK family members
contain an LBE-like insertion that may similarly pack with FATC.

·     
Overview
of mTOR signaling pathway.

mTOR interacts
with many proteins to form at least the two distinct multiprotein mTORC1 and
mTORC2 . The mTOR complexes have differences in their sensitivities to
rapamycin, in the upstream signals they integrate, in the substrates they
regulate, and in the biological process they control. mTORC1 activity is
controlled by the small GTPase Rheb. The GTPase-activating domain of Tuberin
(Tsc2) increases the rate of hydrolysis of Rheb-bound GTP, rendering Rheb to
the inactive GDP-bound form. Tsc2 is inhibited when it is phosphorylated, which
allow Akt to release Rheb from the inhibition by Tsc2 and allows GTP-Rheb to activate
mTORC1 (Fig. 4a). When there is sufficient amino acid and ATP available in the
cell, mTOR is activated. However, when AMPK (plays a role in cellular
homeostasis) is active it inhibits mTOR (Fig.4a). The activation of mTOR
involves the assembly of proteins of the Rag GTPase family at the lysosome. The
best-characterized substrates for mTORC1 are ribosomal S6 kinase (S6K) and the
initiation factor 4E binding protein1 (4E-BP1). The phosphorylated form of S6K
and 4E-BP1 promotes protein synthesis. S6K1phosphorylates and activates several
substrates that promote mRNA translation initiation (Fig. 4b). mTORC1 also
facilitates growth by promoting a shift in glucose metabolism from oxidative
phosphorylation to glycolysis, which facilitates the incorporation of nutrients
into new biomass (Fig.4b). Furthermore, mTORC1 leads to increased flux through
the oxidative pentose phosphate pathway (PPP), which use carbons from glucose
to generate the NADPH and other intermediary metabolites needed for
proliferation and cell growth. In addition, mTORC1 also promotes growth by
suppressing protein catabolism (Fig.2a), precisely autophagy. When the cell is
under starving conditions, mTORC1 phosphorylates ULK1, a kinase that drives autophagosome
formation, which prevents its activation by AMPK (Fig4.b). mTORC1 can also
negatively regulate class I PI3K signaling via different mechanisms, including
phosphorylation of receptors.

While mTORC1
regulates cell growth and metabolism, mTORC2 instead controls proliferation and
survival primarily by phosphorylating several members of the AGC (PKA/PKG/PKC)
family protein kinases (Fig. 4c). Recently, it has been shown that mTORC2 can
also phosphorylate different types of PKCs, which regulates different aspects
of cytoskeletal remodeling and cell migration. Moreover, mTORC2 most important
role is to phosphorylate and activate Akt. Activated Akt plays important roles
in the cell such as cell survival, proliferation, and growth through the
phosphorylation and inhibition of different substrates like Foxo and the mTORC1
inhibitor TSC2 (Fig. 1a). Even-though the signaling pathways that lead to
mTORC2 activation are not well characterized, it is considered that mTORC2
kinase activity and AKT phosphorylation at Ser473 (Fig.4a) increases activity
due to the growth factors. With the growth factors simulation, AKT is
phosphorylated at the cell membrane through the binding of ptdINS to its
pleckstrin homology (PH) domain. Under these conditions, PDK1 is also recruited
to the membrane through its PH domain and phosphorylate AKT at Ser308 (Fig.
4a). 

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