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Identification of key structural motifs in PY‐nuclear localization signals enables design of a pathway selective nuclear import inhibitor
Author(s) -
Cansizoglu Ahmet Ertugrul,
Lee Brittany,
Zhang Zichao,
Fontoura Beatriz,
Chook Yuh Min
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.lb22-b
Subject(s) - nls , nuclear localization sequence , nuclear transport , nuclear export signal , ran , chemistry , microbiology and biotechnology , nuclear protein , nucleus , biochemistry , cell nucleus , biology , gene , transcription factor
Nuclear import of two recently elucidated types of PY‐Nuclear localization signal(NLS) carrying proteins is mediated by Kapβ2/Transportin. PY‐NLSs are divided into hydrophobic(h)PY‐ and basic(b)PY‐NLSs based on the composition of an N‐terminal sequence motif. Biochemical studies in conjunction with the structure of hydrophobic‐PY NLS in complex with Kapβ2 revealed general rules for recognition by Kapβ2: structural disorder, overall positive charge and the loose consensus sequence R/H/KX(2–5)PY. NLS recognition is achieved through two binding epitopes in NLS sequence. Here we present the structure of Kapβ2 in complex with basic‐PY NLS. The biochemical and structural analysis of the two PY‐NLS complex structures enabled the design of a Kapβ2‐specific nuclear import inhibitor. Nuclear import is mediated by dissociation of import complex inside the nucleus by small GTPase Ran. The inhibitor:Kapβ2 complex cannot be efficiently dissociated by Ran.GTP in vitro and blocks the nuclear import of several Kapβ2 import cargoes in vivo .