Sandbox 130

From Proteopedia

Karyopherin-β2

Karyopherinβ is a group of proteins that is composed of both importins and exportins. Importins are proteins that carry cargos into the nucleus while exportins serve the opposite function. As of today, twenty different Kapβs have been identified. Each of these Kapβs is capable of recognizing and transporting a specific group of cargos. In order to bind to its cargo a Kapβ has to recognize a Nuclear Localization or Export Signal (NLS or NES).

Karyopherin beta 2 () is an importin that transports various cargo proteininto the nucleus through interactions with nucleoporins, which are proteins of the nuclear pore complex (NPC). The NPC is a large structure consisting of 456 constituent binding proteins called nucleoporins (Nups). 1 Movement through the NPC is facilitated transport that relies on interaction with specific Nups. Importins and exportins are proteins that aid this facilitated transport by both binding to a specific cargo to be transported and interacting with specific Nups located in the central channel of the NPC.2 One might overlook the significance of this protein but actually plays a crucial role in the human body by mediating transport of RNA- binding proteins involved in transcription, RNA processing, RNA transportand translation. The structure of KAPβ is composed of 20 antiparallel helicescalled HEAT repeats. These HEAT repeats contribute to kapβ2’s largesuperhelical shape. That form two arches: one at the N-terminal and the other at the C- terminal. Through recognition of a Nuclear Localization Signal located on its cargo, kapβ2 binds to its cargo via its C-terminal arch. Release of the cargo is mediated by RanGTP, which once bound, modifies the shape of kapβ2. Release of the cargo is mediated once contact occurs between RanGTP and N-terminal arch of Kapβ2.

The 3D structure of the Kapβ2, highlighed in cornflowerblue, shows one of the 20 HEAT repeats in silver .

How does Kapβ2 identify its cargo?

The NLS located on Kapβ2 cargos are named the PY-NLS and they bind to the C-terminal arch of Kapβ2. The electrostatic potential of the internal surface of Kapβ2 superhelix at the C-terminal arch is negative. Recognition of the PY-NLS by Kapβ2 fallows certain guidelines: (i)PY-NLS, when not bound to Kapβ2, lacks secondary structures. (ii)PY-NLS has an overall positive charge allowing for electrostatic compatibility with Kapβ2. (iii)General sequence for the PY-NLS is either a hydrophobic or basic motif at the N-terminus and a R-X P-Y motif at the C-terminus.

The PY-NLS of 4OO6 contains a basic rather than a hydrophobic N-terminus motif. Basic interactions at the N-terminal motif of the PY-NLS include: of the NLS with Glu588 and Glu496 of Kapβ2. Interactions of the C-terminal R-X P-Y motif of the NLS include: Pro98 of NLS with Ile456 and Trp459 of Kapβ2: Pro98 and Tyr99 of the NLS with Ala381, Ala421, Ile456, Trp459 of Kapβ2.

Upon binding Kapβ2, the NLS gains structure conforms to and makes contacts with the internal surface of the Kapβ2 C-terminal arch.