# BAIAP2

## Overview
BAIAP2, also known as the BAI1-associated protein 2, is a gene that encodes the BAR/IMD domain containing adaptor protein 2, commonly referred to as IRSp53. This protein is a multi-domain scaffolding and adaptor protein that plays a pivotal role in the regulation of actin cytoskeleton dynamics and membrane remodeling. It is characterized by its I-BAR domain, which is essential for membrane binding and deformation, and its SH3 domain, which facilitates interactions with various actin-modulating proteins (Kast2019Mechanism; Kang2016IRSp53BAIAP2). BAIAP2 is involved in critical cellular processes such as the formation and maintenance of dendritic spines, which are vital for synaptic signaling and plasticity in neurons (Kang2016IRSp53BAIAP2). The protein's interactions with small GTPases and other synaptic proteins underscore its importance in synaptic function and neuronal connectivity. Alterations in the BAIAP2 gene have been linked to several psychiatric disorders, highlighting its clinical significance in neurodevelopmental and neuropsychiatric conditions (Hasler2017Interhemispherical; Kang2016IRSp53BAIAP2).

## Structure
BAIAP2, also known as IRSp53, is a multi-domain adaptor protein involved in actin cytoskeleton remodeling and membrane dynamics. The protein contains several distinct domains that contribute to its function. At the N-terminus, BAIAP2 features an I-BAR domain (residues 1-231), which is crucial for membrane binding and deformation, creating negative membrane curvature (Kast2019Mechanism; Kang2016IRSp53BAIAP2). Following the I-BAR domain is a CRIB-PR domain (residues 260-291), which includes a partial CRIB motif interrupted by a proline-rich sequence. This domain is involved in binding the small GTPase Cdc42 (Kast2019Mechanism; Kang2016IRSp53BAIAP2).

The SH3 domain (residues 375-437) is located at the C-terminus and is responsible for interactions with proline-rich motifs in downstream cytoskeletal effectors (Oda1999Identification; Kast2019Mechanism). The region between the CRIB-PR and SH3 domains contains multiple phosphorylation sites, which are involved in binding regulatory proteins like 14-3-3, influencing the protein's conformation and activity (Kast2019Mechanism).

BAIAP2 undergoes alternative splicing, resulting in multiple isoforms, including BAIAP2-a and BAIAP2-β, which differ slightly in their amino acid sequences (Oda1999Identification). These structural features enable BAIAP2 to play a significant role in cellular signaling and cytoskeletal organization.

## Function
BAIAP2, also known as IRSp53, is a multi-domain scaffolding and adaptor protein that plays a crucial role in the regulation of membrane and actin dynamics at subcellular structures such as filopodia and lamellipodia. It is involved in the formation and maintenance of dendritic spines, which are actin-rich structures in neurons essential for synaptic signaling and plasticity (Kang2016IRSp53BAIAP2). BAIAP2 interacts with small GTPases and actin regulatory proteins, facilitating membrane deformation and actin filament bundling, which are critical for cell shape and motility (Kang2016IRSp53BAIAP2).

In the brain, BAIAP2 is a component of the postsynaptic density at excitatory synapses, where it interacts with NMDA receptors and other synaptic proteins such as PSD-95, influencing synaptic strength and plasticity (Kang2016IRSp53BAIAP2). The protein's activity is regulated by neuronal activity and NMDA receptor stimulation, impacting synaptic localization and function (Kang2016IRSp53BAIAP2).

BAIAP2 is also involved in maintaining cellular homeostasis by interacting with Robo2 to regulate p53 activity, which is essential for preventing premature senescence and supporting proper cell differentiation and polarization (Li2019Disruption). This interaction is crucial for processes such as ciliogenesis and epithelial differentiation, particularly in renal epithelial cells (Li2019Disruption).

## Clinical Significance
Mutations and alterations in the expression of the BAIAP2 gene, also known as IRSp53, have been implicated in several psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), and schizophrenia. In ADHD, specific single nucleotide polymorphisms (SNPs) within BAIAP2, such as rs8079626, have been associated with functional connectivity asymmetry in the brain's default-mode network, influencing emotional regulation and anger expression (Hasler2017Interhemispherical). 

In the context of ASDs and schizophrenia, genetic variations such as SNPs and de novo copy number variations (CNVs) that affect the BAIAP2 gene have been identified. These genetic alterations can lead to changes in synaptic transmission and neuronal connectivity, contributing to the symptoms observed in these disorders (Kang2016IRSp53BAIAP2). 

Research on IRSp53 knockout mice has shown that the absence of this gene results in enhanced NMDA receptor function, which is linked to social and cognitive deficits. These deficits can be ameliorated by pharmacological interventions targeting NMDA receptor activity, suggesting a potential therapeutic avenue for conditions associated with BAIAP2 dysfunction (Kang2016IRSp53BAIAP2).

## Interactions
BAIAP2, also known as IRSp53, is involved in various protein interactions that are crucial for its role in actin cytoskeleton remodeling and cell signaling. It interacts with small GTPases such as Rac1 and Cdc42, which are important for dendritic spine morphogenesis and synaptic plasticity (Choi2005Regulation; Kang2016IRSp53BAIAP2). The CRIB-PR domain of BAIAP2 binds to activated Cdc42, facilitating its targeting to the plasma membrane and promoting synaptogenesis (Kang2016IRSp53BAIAP2).

BAIAP2 also interacts with actin-modulating proteins like WAVE2, N-WASP, and Eps8 through its SH3 domain, which is essential for actin filament network formation and the regulation of dendritic spine morphology (Choi2005Regulation; Kang2016IRSp53BAIAP2). It forms complexes with postsynaptic density proteins such as PSD-95 and Shank, influencing synaptic localization and function (Choi2005Regulation; Kang2016IRSp53BAIAP2).

In the context of renal cystic diseases, BAIAP2 interacts with Robo2, forming a signaling complex that regulates epithelial cell development and ciliogenesis (Li2019Disruption). This interaction is crucial for maintaining p53 stability and normal kidney function (Li2019Disruption). BAIAP2's interaction with tau proteins has also been observed, suggesting a role in synaptic pathogenesis in Alzheimer's disease (Sinsky2020Physiological).


## References


[1. (Oda1999Identification) K. Oda, T. Shiratsuchi, H. Nishimori, J. Inazawa, H. Yoshikawa, Y. Taketani, Y. Nakamura, and T. Tokino. Identification of baiap2 (bai-associated protein 2), a novel human homologue of hamster irsp53, whose sh3 domain interacts with the cytoplasmic domain of bai1. Cytogenetic and Genome Research, 84(1–2):75–82, 1999. URL: http://dx.doi.org/10.1159/000015219, doi:10.1159/000015219. This article has 71 citations and is from a peer-reviewed journal.](https://doi.org/10.1159/000015219)

[2. (Hasler2017Interhemispherical) R. Hasler, M.G. Preti, D.E. Meskaldji, J. Prados, W. Adouan, C. Rodriguez, S. Toma, N. Hiller, T. Ismaili, J. Hofmeister, I. Sinanaj, P. Baud, S. Haller, P. Giannakopoulos, S. Schwartz, N. Perroud, and D. Van De Ville. Inter-hemispherical asymmetry in default-mode functional connectivity and baiap2 gene are associated with anger expression in adhd adults. Psychiatry Research: Neuroimaging, 269:54–61, November 2017. URL: http://dx.doi.org/10.1016/j.pscychresns.2017.09.004, doi:10.1016/j.pscychresns.2017.09.004. This article has 17 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.pscychresns.2017.09.004)

[3. (Kast2019Mechanism) David J. Kast and Roberto Dominguez. Mechanism of irsp53 inhibition by 14-3-3. Nature Communications, January 2019. URL: http://dx.doi.org/10.1038/s41467-019-08317-8, doi:10.1038/s41467-019-08317-8. This article has 53 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-019-08317-8)

[4. (Choi2005Regulation) Jeonghoon Choi, Jaewon Ko, Bence Racz, Alain Burette, Jae-Ran Lee, Seho Kim, Moonseok Na, Hyun Woo Lee, Karam Kim, Richard J. Weinberg, and Eunjoon Kim. Regulation of dendritic spine morphogenesis by insulin receptor substrate 53, a downstream effector of rac1 and cdc42 small gtpases. The Journal of Neuroscience, 25(4):869–879, January 2005. URL: http://dx.doi.org/10.1523/jneurosci.3212-04.2005, doi:10.1523/jneurosci.3212-04.2005. This article has 191 citations.](https://doi.org/10.1523/jneurosci.3212-04.2005)

[5. (Li2019Disruption) Qinggang Li, Shaoyuan Cui, Qian Ma, Ying Liu, Hongyu Yu, GuangRui Geng, Ewud Agborbesong, Chongyu Ren, Kai Wei, Yingjie Zhang, Jurong Yang, Xueyuan Bai, Guangyan Cai, Yuansheng Xie, Xiaogang Li, and Xiangmei Chen. Disruption of robo2-baiap2 integrated signaling drives cystic disease. JCI Insight, September 2019. URL: http://dx.doi.org/10.1172/jci.insight.127602, doi:10.1172/jci.insight.127602. This article has 5 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1172/jci.insight.127602)

[6. (Sinsky2020Physiological) Jakub Sinsky, Petra Majerova, Andrej Kovac, Max Kotlyar, Igor Jurisica, and Jozef Hanes. Physiological tau interactome in brain and its link to tauopathies. Journal of Proteome Research, 19(6):2429–2442, May 2020. URL: http://dx.doi.org/10.1021/acs.jproteome.0c00137, doi:10.1021/acs.jproteome.0c00137. This article has 24 citations and is from a peer-reviewed journal.](https://doi.org/10.1021/acs.jproteome.0c00137)

[7. (Kang2016IRSp53BAIAP2) Jaeseung Kang, Haram Park, and Eunjoon Kim. Irsp53/baiap2 in dendritic spine development, nmda receptor regulation, and psychiatric disorders. Neuropharmacology, 100:27–39, January 2016. URL: http://dx.doi.org/10.1016/j.neuropharm.2015.06.019, doi:10.1016/j.neuropharm.2015.06.019. This article has 74 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.neuropharm.2015.06.019)