Related Experiment Video
Updated: Jul 15, 2026
12:13
Single-Molecule Imaging of Nuclear Transport
Published on: June 9, 2010
Structure-based design of a pathway-specific nuclear import inhibitor
Ahmet E Cansizoglu1, Brittany J Lee, Zi Chao Zhang
1Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park, Dallas, Texas 75390-9041, USA.
Nature Structural & Molecular Biology
|April 17, 2007
Summary
Karyopherin beta2 (Kapbeta2) recognizes a novel class of nuclear localization signals (NLSs) called PY-NLSs. Structural analysis revealed conserved motifs explaining Kapbeta2
Area of Science:
- Molecular Biology
- Structural Biology
- Biochemistry
Background:
- Karyopherin beta2 (Kapbeta2), also known as transportin, is a key protein involved in nuclear transport.
- It recognizes a specific class of nuclear localization signals (NLSs) termed PY-NLSs, characterized by the R/H/Kx((2-5))PY motif.
Purpose of the Study:
- To elucidate the structural basis for Kapbeta2's recognition of diverse PY-NLSs.
- To understand how structural convergence at consensus motifs explains ligand diversity.
- To design a specific inhibitor for Kapbeta2-mediated nuclear import.
Main Methods:
- Structural analysis of Kapbeta2 complexes with PY-NLSs.
- Biochemical analyses to complement structural data.
Main Results:
- Kapbeta2 complexes with hydrophobic and basic PY-NLSs converge structurally at conserved consensus motifs.
- This structural convergence explains the broad ligand diversity recognized by Kapbeta2.
- A novel Kapbeta2-specific nuclear import inhibitor, M9M, was designed based on these findings.
Conclusions:
- The study reveals the structural mechanisms underlying Kapbeta2's recognition of PY-NLSs.
- Understanding these mechanisms facilitates the design of targeted nuclear import inhibitors.
- M9M represents a potential tool for studying or inhibiting Kapbeta2 function.
Related Concept Videos
01:46Nuclear Localization Signals and Import
Proteins targeted to the nucleus carry short stretches of amino acid sequences called the nuclear localization signal or NLS. Classical nuclear localization signals are of two types: monopartite and bipartite NLS. Monopartite classical NLS (cNLS) consists of a single cluster of 4-8 amino acids. Bipartite cNLS consists of two clusters of 2-3 amino acids and a 9-12 residue long proline-rich linker bridging the two clusters. Signal clusters are rich in positively charged amino acids such as...
01:45Regulation of Nuclear Protein Sorting
Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
01:34Nuclear Protein Sorting
Nuclear protein sorting is the selective trafficking of histones, polymerases, gene regulatory proteins into the nucleus and exporting RNAs and ribosomes to the cytosol. It is a tightly controlled process that regulates gene expression within a cell.
Proteins targeted to the nucleus carry nuclear localization signals or NLS recognized by import receptors in the cytosol. Similarly, proteins with nuclear export signals are recognized by export receptors. Import and export receptors are...
Proteins targeted to the nucleus carry nuclear localization signals or NLS recognized by import receptors in the cytosol. Similarly, proteins with nuclear export signals are recognized by export receptors. Import and export receptors are...
01:42Directionality of Nuclear Transport
Ras-related nuclear protein or Ran is a small G protein that cycles between its GTP and GDP bound states. Ran specific regulators, a Ran GTPase Activating Protein or RanGAP present in the cytosol and a Ran guanine nucleotide exchange factor or RanGEF present inside the nucleus regulate GTP/GDP exchange. A high concentration of GTP inside the cells, in addition to this asymmetric distribution of Ran-specific regulators, leads to a higher RanGTP concentration inside the nucleus. This...
01:42Nuclear Export
The nucleus restricts several proteins within and allows others to pass. The restricted proteins possess a nuclear retention sequence or NRS, anchoring them to the nuclear lamins and preventing their transport to the cytosol. The non-restricted proteins, after their synthesis, are transported to their site of action, such as the cytosol or other organelles, with the help of nuclear export signals or NES.
NES are of three types- the canonical 10-residue long leucine-rich signal and other...
NES are of three types- the canonical 10-residue long leucine-rich signal and other...
01:39Mitochondrial Protein Sorting
Mitochondria are double-membrane organelles of the eukaryotes involved in cellular metabolism, signaling, ATP synthesis, and programmed cell death. Each of these processes requires specific proteins and enzymes that must be correctly sorted to the right mitochondrial subcompartment for the proper functioning of the organelle.
Most of these mitochondrial proteins are encoded by the nucleus and imported to the mitochondria as unfolded or loosely folded precursors. Mitochondrial precursors...
Most of these mitochondrial proteins are encoded by the nucleus and imported to the mitochondria as unfolded or loosely folded precursors. Mitochondrial precursors...